Junta de Castilla y León

OBJECTIVE: To evaluate the pharmacokinetics of a novel commercial formulation of ivermectin after administration to goats. ANIMALS: 6 healthy adult goats. PROCEDURE: Ivermectin (200 microg/kg) was initially administered IV to each goat, and plasma samples were obtained for 36 days. After a washout period of 3 weeks, each goat received a novel commercial formulation of ivermectin (200 microg/kg) by SC injection. Plasma samples were then obtained for 42 days. Drug concentrations were quantified by use of high-performance liquid chromatography with fluorescence detection. RESULTS: Pharmacokinetics of ivermectin after IV administration were best described by a 2-compartment open model; values for main compartmental variables included volume of distribution at a steady state (9.94 L/kg), clearance (1.54 L/kg/d), and area under the plasma concentration-time curve (AUC; 143 [ng x d]/mL). Values for the noncompartmental variables included mean residence time (7.37 days), AUC (153 [ng x d]/mL), and clearance (1.43 L/kg/d). After SC administration, noncompartmental pharmacokinetic analysis was conducted. Values of the variables calculated by use of this method included maximum plasma concentration (Cmax; 21.8 ng/mL), time to reach Cmax (3 days), and bioavailability (F; 91.8%). CONCLUSIONS AND CLINICAL RELEVANCE: The commercial formulation used in this study is a good option to consider when administering ivermectin to goats because of the high absorption, which is characterized by high values of F. In addition, the values of Cmax and time to reach Cmax are higher than those reported by other investigators who used other routes of administration.

Abstract Body-mass index (BMI) has increased steadily in most countries in parallel with a rise in the proportion of the population who live in cities 1,2 . This has led to a widely reported view that urbanization is one of the most important drivers of the global rise in obesity 3–6 . Here we use 2,009 population-based studies, with measurements of height and weight in more than 112 million adults, to report national, regional and global trends in mean BMI segregated by place of residence (a rural or urban area) from 1985 to 2017. We show that, contrary to the dominant paradigm, more than 55% of the global rise in mean BMI from 1985 to 2017—and more than 80% in some low- and middle-income regions—was due to increases in BMI in rural areas. This large contribution stems from the fact that, with the exception of women in sub-Saharan Africa, BMI is increasing at the same rate or faster in rural areas than in cities in low- and middle-income regions. These trends have in turn resulted in a closing—and in some countries reversal—of the gap in BMI between urban and rural areas in low- and middle-income countries, especially for women. In high-income and industrialized countries, we noted a persistently higher rural BMI, especially for women. There is an urgent need for an integrated approach to rural nutrition that enhances financial and physical access to healthy foods, to avoid replacing the rural undernutrition disadvantage in poor countries with a more general malnutrition disadvantage that entails excessive consumption of low-quality calories.

Several studies have characterized the cellular and molecular mechanisms of hepatocyte injury caused by the retention of hydrophobic bile acids (BAs) in cholestatic diseases. BAs may disrupt cell membranes through their detergent action on lipid components and can promote the generation of reactive oxygen species that, in turn, oxidatively modify lipids, proteins, and nucleic acids, and eventually cause hepatocyte necrosis and apoptosis. Several pathways are involved in triggering hepatocyte apoptosis. Toxic BAs can activate hepatocyte death receptors directly and induce oxidative damage, thereby causing mitochondrial dysfunction, and induce endoplasmic reticulum stress. When these compounds are taken up and accumulate inside biliary cells, they can also cause apoptosis. Regarding extrahepatic tissues, the accumulation of BAs in the systemic circulation may contribute to endothelial injury in the kidney and lungs. In gastrointestinal cells, BAs may behave as cancer promoters through an indirect mechanism involving oxidative stress and DNA damage, as well as acting as selection agents for apoptosis-resistant cells. The accumulation of BAs may have also deleterious effects on placental and fetal cells. However, other BAs, such as ursodeoxycholic acid, have been shown to modulate BA-induced injury in hepatocytes. The major beneficial effects of treatment with ursodeoxycholic acid are protection against cytotoxicity due to more toxic BAs; the stimulation of hepatobiliary secretion; antioxidant activity, due in part to an enhancement in glutathione levels; and the inhibition of liver cell apoptosis. Other natural BAs or their derivatives, such as cholyl-N-methylglycine or cholylsarcosine, have also aroused pharmacological interest owing to their protective properties.

We assembled genome-wide data from 271 ancient Iberians, of whom 176 are from the largely unsampled period after 2000 BCE, thereby providing a high-resolution time transect of the Iberian Peninsula. We document high genetic substructure between northwestern and southeastern hunter-gatherers before the spread of farming. We reveal sporadic contacts between Iberia and North Africa by ~2500 BCE and, by ~2000 BCE, the replacement of 40% of Iberia's ancestry and nearly 100% of its Y-chromosomes by people with Steppe ancestry. We show that, in the Iron Age, Steppe ancestry had spread not only into Indo-European-speaking regions but also into non-Indo-European-speaking ones, and we reveal that present-day Basques are best described as a typical Iron Age population without the admixture events that later affected the rest of Iberia. Additionally, we document how, beginning at least in the Roman period, the ancestry of the peninsula was transformed by gene flow from North Africa and the eastern Mediterranean.

There is no clear agreement regarding the ideal combination of factors needed to optimize postactivation potentiation (PAP) after a conditioning activity. Therefore, a meta-analysis was conducted to evaluate the effects of training status, volume, rest period length, conditioning activity, and gender on power augmentation due to PAP. A total of 141 effect sizes (ESs) for muscular power were obtained from a total of 32 primary studies, which met our criteria of investigating the effects of a heavy preconditioning activity on power in randomized human trials. The mean overall ES for muscle power was 0.38 after a conditioning activity (p < 0.05). Significant differences were found between moderate intensity (60-84%) 1.06 and heavy intensity (>85%) 0.31 (p < 0.05). There were overall significant differences found between single sets 0.24 and multiple sets 0.66 (p < 0.05). Rest periods of 7-10 minutes (0.7) after a conditioning activity resulted in greater ES than 3-7 minutes (0.54), which was greater than rest periods of >10 minutes (0.02) (p < 0.05). Significant differences were found between untrained 0.14 and athletes 0.81 and between trained 0.29 and athletes. The primary findings of this study were that a conditioning activity augmented power output, and these effects increased with training experience, but did not differ significantly between genders. Moreover, potentiation was optimal after multiple (vs. single) sets, performed at moderate intensities, and using moderate rest periods lengths (7-10 minutes).

BACKGROUND: Mesenchymal stromal cells are a promising option to treat knee osteoarthritis. Their safety and usefulness must be confirmed and the optimal dose established. We tested increasing doses of bone marrow mesenchymal stromal cells (BM-MSCs) in combination with hyaluronic acid in a randomized clinical trial. MATERIALS: A phase I/II multicenter randomized clinical trial with active control was conducted. Thirty patients diagnosed with knee OA were randomly assigned to intraarticularly administered hyaluronic acid alone (control), or together with 10 × 10(6) or 100 × 10(6) cultured autologous BM-MSCs, and followed up for 12 months. Pain and function were assessed using VAS and WOMAC and by measuring the knee motion range. X-ray and magnetic resonance imaging analyses were performed to analyze joint damage. RESULTS: No adverse effects were reported after BM-MSC administration or during follow-up. BM-MSC-administered patients improved according to VAS during all follow-up evaluations and median value (IQR) for control, low-dose and high-dose groups change from 5 (3, 7), 7 (5, 8) and 6 (4, 8) to 4 (3, 5), 2 (1, 3) and 2 (0,4) respectively at 12 months (low-dose vs control group p = 0.005 and high-dose vs control group p < 0.009). BM-MSC-administered patients were also superior according to WOMAC, although improvement in control and low-dose patients could not be significantly sustained beyond 6 months. On the other hand, the BM-MSC high-dose group exhibited an improvement of 16.5 (12, 19) points at 12 months (p < 0.01). Consistent with WOMAC and VAS values, motion ranges remained unaltered in the control group but improved at 12 months with BM-MSCs. X-ray revealed a reduction of the knee joint space width in the control group that was not seen in BM-MSCs high-dose group. MRI (WORMS protocol) showed that joint damage decreased only in the BM-MSC high-dose group, albeit slightly. CONCLUSIONS: The single intraarticular injection of in vitro expanded autologous BM-MSCs together with HA is a safe and feasible procedure that results in a clinical and functional improvement of knee OA, especially when 100 × 10(6) cells are administered. These results pave the way for a future phase III clinical trial. CLINICAL TRIALS: gov identifier NCT02123368. Nº EudraCT: 2009-017624-72.

Abstract High blood cholesterol is typically considered a feature of wealthy western countries 1,2 . However, dietary and behavioural determinants of blood cholesterol are changing rapidly throughout the world 3 and countries are using lipid-lowering medications at varying rates. These changes can have distinct effects on the levels of high-density lipoprotein (HDL) cholesterol and non-HDL cholesterol, which have different effects on human health 4,5 . However, the trends of HDL and non-HDL cholesterol levels over time have not been previously reported in a global analysis. Here we pooled 1,127 population-based studies that measured blood lipids in 102.6 million individuals aged 18 years and older to estimate trends from 1980 to 2018 in mean total, non-HDL and HDL cholesterol levels for 200 countries. Globally, there was little change in total or non-HDL cholesterol from 1980 to 2018. This was a net effect of increases in low- and middle-income countries, especially in east and southeast Asia, and decreases in high-income western countries, especially those in northwestern Europe, and in central and eastern Europe. As a result, countries with the highest level of non-HDL cholesterol—which is a marker of cardiovascular risk—changed from those in western Europe such as Belgium, Finland, Greenland, Iceland, Norway, Sweden, Switzerland and Malta in 1980 to those in Asia and the Pacific, such as Tokelau, Malaysia, The Philippines and Thailand. In 2017, high non-HDL cholesterol was responsible for an estimated 3.9 million (95% credible interval 3.7 million–4.2 million) worldwide deaths, half of which occurred in east, southeast and south Asia. The global repositioning of lipid-related risk, with non-optimal cholesterol shifting from a distinct feature of high-income countries in northwestern Europe, north America and Australasia to one that affects countries in east and southeast Asia and Oceania should motivate the use of population-based policies and personal interventions to improve nutrition and enhance access to treatment throughout the world.

<h3>Background</h3> Humoral immunocompetence develops stepwise throughout life and contributes to individual susceptibility to infection, immunodeficiency, autoimmunity, and neoplasia. Immunoglobulin heavy chain (IgH) isotype serum levels can partly explain such age-related differences, but their relationship with the IgH isotype distribution within memory B-cell (MBC) and plasma cell (PCs) compartments remains to be investigated. <h3>Objective</h3> We studied the age-related distribution of MBCs and PCs expressing different IgH isotypes in addition to the immature/transitional and naive B-cell compartments. <h3>Methods</h3> B-cell and PC subsets and plasma IgH isotype levels were studied in cord blood (n = 19) and peripheral blood (n = 215) from healthy donors aged 0 to 90 years by using flow cytometry and nephelometry, respectively. <h3>Results</h3> IgH-switched MBCs expressing IgG₁, IgG₂, IgG₃, IgA₁, and IgA₂ were already detected in cord blood and newborns at very low counts, whereas CD27⁺IgM⁺⁺IgD⁺ MBCs only became detectable at 1 to 5 months and remained stable until 2 to 4 years, and IgD MBCs peaked at 2 to 4 years, with both populations decreasing thereafter. MBCs expressing IgH isotypes of the second immunoglobulin heavy chain constant region <i>(IGHC)</i> gene block (IgG₁, IgG₃, and IgA₁) peaked later during childhood (2-4 years), whereas MBCs expressing third <i>IGHC</i> gene block immunoglobulin isotypes (IgG₂, IgG₄, and IgA₂) reached maximum values during adulthood. PCs were already detected in newborns, increasing in number until 6 to 11 months for IgM, IgG₁, IgG₂, IgG₃, IgA₁, and IgA₂; until 2 to 4 years for IgD; and until 5 to 9 years for IgG₄ and decreasing thereafter. For most IgH isotypes (except IgD and IgG₄), maximum plasma levels were reached after PC and MBC counts peaked. <h3>Conclusions</h3> PC counts reach maximum values early in life, followed by MBC counts and plasma IgH isotypes. Importantly, IgH isotypes from different <i>IGHC</i> gene blocks show different patterns, probably reflecting consecutive cycles of IgH isotype switch recombination through life.

BACKGROUND: It is now established that certain types of human papillomaviruses (HPVs) are the sexually transmitted agents etiologically linked to cervical cancer. Studies assessing the contribution of the male's sexual behavior and genital HPV DNA status to the risk of development of cervical neoplasia in sexual partners have yielded inconsistent results. PURPOSE: This study evaluates the role of men's sexual behavior and the presence of HPV DNA in the penis on the development of cervical cancer in their sexual partners in Spain, a low-risk area for cervical neoplasia. METHODS: Husbands (n = 633) of women participating in two case-control studies of cervical neoplasia were interviewed to obtain information on lifestyle habits, including sexual practices. Cytologic samples were taken from the distal urethra and the surface of the glans penis of 183 husbands of case women and of 171 husbands of control women. These samples were analyzed by a polymerase chain reaction-based system using a generic probe and 25 type-specific probes for the detection and typing of HPV DNA. Serologic specimens were also obtained and analyzed for antibodies to Chlamydia trachomatis, Treponema pallidum, herpes simplex virus type II, and Neisseria gonorrhoeae. RESULTS: The presence of HPV DNA in the husbands' penis conveyed a fivefold risk of cervical cancer to their wives (adjusted odds ratio [OR] for HPV DNA positivity = 4.9; 95% confidence interval [CI] = 1.9-12.6). The risk of cervical cancer was strongly related to HPV type (adjusted OR for HPV type 16 = 9.0; 95% CI = 1.1-77.5), to the husbands' number of extramarital partners (adjusted OR = 11.0; 95% CI = 3.0-40.0; for > or = 21 women versus one), and to the number of prostitutes as extramarital sexual partners (adjusted OR = 8.0; 95% CI = 2.9-22.2; for > or = 10 women versus none). Presence of antibodies to C. trachomatis (adjusted OR = 2.6; 95% CI = 1.4-4.6) and an early age at first sexual intercourse of the husband (adjusted OR = 3.2; 95% CI = 1.7-5.9; for < or = 15 years versus > or = 21 years) were also associated with cervical neoplasia in the wife. After adjustment for these variables and for the wife's pack-years of smoking, the husband's smoking was moderately associated with cervical cancer in his wife (adjusted OR = 2.5; 95% CI = 1.4-4.4; for > or = 26.2 pack-years versus none). CONCLUSIONS: The study supports the role of men as vectors of the HPV types that are related to cervical cancer. Life-time number of female sexual partners, number of female prostitutes as sexual partners, and detection of HPV DNA in the penis of husbands are all surrogate markers of exposure to HPV during marriage. IMPLICATIONS: Men who report multiple sexual partners or who are carriers of HPV DNA may be vectors of high-risk HPV types and may place their wives at high risk of developing cervical cancer. Prostitutes are an important reservoir of high-risk HPVs.

Monoclonal B-cell lymphocytosis (MBL) indicates the presence of less than 5 x 10(9)/L circulating monoclonal B cells in otherwise healthy subjects. Recently, it has been reported that circulating chronic lymphocytic leukemia (CLL)-like B cells can be detected using 4- or 5-multicolor flow cytometry in 5% to 7% of adults with normal lymphocyte counts. We investigated the frequency of circulating monoclonal B cells in 608 healthy subjects older than 40 years with normal blood counts, using a highly sensitive 8-color flow cytometry approach and systematic screening for total PB leukocyte count higher than 5 x 10(6). We show that the frequency of PB monoclonal B cells is markedly higher than previously reported (12% for CLL-like B cells, found at frequencies of 0.17 +/- 0.13 x 10(9) cells/L), the incidence progressively increasing with age. Most cases (62%) showed clonal B-cell levels below the maximum sensitivity of the techniques described by others (< 0.01%), supporting the notion that detection of MBL may largely depend on the sensitivity of the flow cytometry approach used.

A review on the impact of radiofrequency radiation from wireless telecommunications on wildlife is presented. Electromagnetic radiation is a form of environmental pollution which may hurt wildlife. Phone masts located in their living areas are irradiating continuously some species that could suffer long-term effects, like reduction of their natural defenses, deterioration of their health, problems in reproduction and reduction of their useful territory through habitat deterioration. Electromagnetic radiation can exert an aversive behavioral response in rats, bats and birds such as sparrows. Therefore microwave and radiofrequency pollution constitutes a potential cause for the decline of animal populations and deterioration of health of plants living near phone masts. To measure these effects urgent specific studies are necessary.

BACKGROUND: Timely influenza surveillance is important to monitor influenza epidemics. OBJECTIVES: (i) To calculate the epidemic threshold for influenza-like illness (ILI) and acute respiratory infections (ARI) in 19 countries, as well as the thresholds for different levels of intensity. (ii) To evaluate the performance of these thresholds. METHODS: The moving epidemic method (MEM) has been developed to determine the baseline influenza activity and an epidemic threshold. False alerts, detection lags and timeliness of the detection of epidemics were calculated. The performance was evaluated using a cross-validation procedure. RESULTS: The overall sensitivity of the MEM threshold was 71·8% and the specificity was 95·5%. The median of the timeliness was 1 week (range: 0-4·5). CONCLUSIONS: The method produced a robust and specific signal to detect influenza epidemics. The good balance between the sensitivity and specificity of the epidemic threshold to detect seasonal epidemics and avoid false alerts has advantages for public health purposes. This method may serve as standard to define the start of the annual influenza epidemic in countries in Europe.

Abstract Critical illness in COVID-19 is an extreme and clinically homogeneous disease phenotype that we have previously shown 1 to be highly efficient for discovery of genetic associations 2 . Despite the advanced stage of illness at presentation, we have shown that host genetics in patients who are critically ill with COVID-19 can identify immunomodulatory therapies with strong beneficial effects in this group 3 . Here we analyse 24,202 cases of COVID-19 with critical illness comprising a combination of microarray genotype and whole-genome sequencing data from cases of critical illness in the international GenOMICC (11,440 cases) study, combined with other studies recruiting hospitalized patients with a strong focus on severe and critical disease: ISARIC4C (676 cases) and the SCOURGE consortium (5,934 cases). To put these results in the context of existing work, we conduct a meta-analysis of the new GenOMICC genome-wide association study (GWAS) results with previously published data. We find 49 genome-wide significant associations, of which 16 have not been reported previously. To investigate the therapeutic implications of these findings, we infer the structural consequences of protein-coding variants, and combine our GWAS results with gene expression data using a monocyte transcriptome-wide association study (TWAS) model, as well as gene and protein expression using Mendelian randomization. We identify potentially druggable targets in multiple systems, including inflammatory signalling ( JAK1 ), monocyte–macrophage activation and endothelial permeability ( PDE4A ), immunometabolism ( SLC2A5 and AK5 ), and host factors required for viral entry and replication ( TMPRSS2 and RAB2A ).

BACKGROUND: Vast sample sizes are often essential in the quest to disentangle the complex interplay of the genetic, lifestyle, environmental and social factors that determine the aetiology and progression of chronic diseases. The pooling of information between studies is therefore of central importance to contemporary bioscience. However, there are many technical, ethico-legal and scientific challenges to be overcome if an effective, valid, pooled analysis is to be achieved. Perhaps most critically, any data that are to be analysed in this way must be adequately 'harmonized'. This implies that the collection and recording of information and data must be done in a manner that is sufficiently similar in the different studies to allow valid synthesis to take place. METHODS: This conceptual article describes the origins, purpose and scientific foundations of the DataSHaPER (DataSchema and Harmonization Platform for Epidemiological Research; http://www.datashaper.org), which has been created by a multidisciplinary consortium of experts that was pulled together and coordinated by three international organizations: P³G (Public Population Project in Genomics), PHOEBE (Promoting Harmonization of Epidemiological Biobanks in Europe) and CPT (Canadian Partnership for Tomorrow Project). RESULTS: The DataSHaPER provides a flexible, structured approach to the harmonization and pooling of information between studies. Its two primary components, the 'DataSchema' and 'Harmonization Platforms', together support the preparation of effective data-collection protocols and provide a central reference to facilitate harmonization. The DataSHaPER supports both 'prospective' and 'retrospective' harmonization. CONCLUSION: It is hoped that this article will encourage readers to investigate the project further: the more the research groups and studies are actively involved, the more effective the DataSHaPER programme will ultimately be.

To analyze the intra- and inter-instrument reliability of the ActiGraph GT3X accelerometer using a vibration table on each orthogonal axis and at five frequencies of motion. Ten GT3X units were subjected to a specific vibration using a motorized vibration table along the vertical, horizontal right-left and horizontal front-back axis, and at 1.1, 2.1, 3.1, 4.1 and 10.2 Hz. The 5 min data for each frequency were analyzed separately for frequency, axis effects, and inter- and intra-instrument variability. We found overall high intra-and inter-instrument reliability for the GT3X accelerometer at frequencies between 2.1 and 4.1 Hz. For frequencies ranging between 2.1 and 4.1 Hz, the intra-instrument coefficient of variation was ≤2.5%. The inter-instrument coefficient of variation ranged widely along axes and frequencies, with the lowest values (≤9%) corresponding to 2.1-4.1 Hz. The intra-class correlation coefficient for activity counts across frequencies and for all axes was 0.97. Overall, our findings support the use of the GT3X accelerometer as an accurate tool to estimate free-living physical activity, at least within those frequencies that are common to most types of human daily activities.

AbstractBackground: Cooperative Learning has been recently defined as a true pedagogical model. Moreover, in a recent review Casey and Goodyear reported that it can help physical education promote the four basic learning outcomes: physical, cognitive, social and affective.Purpose: The main goal was to investigate the impact of a sustained Cooperative Learning intervention on student motivation. The second goal was to assess students’ perceptions of the Cooperative Learning class climate. Finally, the third goal was to explore students’ feelings and thoughts after experiencing Cooperative Learning in physical education for an extended period of time.Participants and settings: 249 students (grades 8–11) and 4 teachers enrolled in 4 different high schools agreed to participate. Each school administration allocated several class groups to each teacher based on its necessities. Therefore, intact physical education classes played a part in this research project. They were randomly distributed into an experimental group with 137 students (mean age 13.91 ± 1.76 years), which experienced 3 consecutive cooperative learning units, and a comparison group with 112 students (mean age 13.41 ± 1.25 years), which experienced a traditional teaching approach during the same length of time.Research design: A pre-test, post-test, quasi-experimental, comparison group design was followed.Data collection: Prior to and at the end of the intervention programme, all participating students were asked to complete a questionnaire, which included the Perceived Locus of Causality Scale and the subscale ‘Cooperative Learning’ of the Perceived Motivational Climate Questionnaire. At post-test, participants in the experimental group were also asked to: ‘Describe your feelings, your thoughts and your ideas on the three Cooperative Learning units that you just experienced in physical education’.Data analysis: Quantitative data was analysed using SPSS 22.0, while MAXQDA 11 was used to assist with qualitative data management.Findings: Quantitative data showed an increase in intrinsic motivation and identified regulation only in the experimental group. This group also increased its perceptions of a Cooperative Learning class climate. Qualitative data analysis of the students’ responses after experiencing Cooperative Learning on a sustained basis produced five major themes: cooperation, relatedness, enjoyment, novelty and disappointment. All these findings are in line with Vallerand's hierarchical model of motivation, where social factors (i.e. Cooperative Learning) influence psychological mediators (i.e. relatedness), which mediate over the different types of motivation (i.e. intrinsic motivation) and finally lead to different outcomes (i.e. enjoyment).Conclusion: Cooperative Learning applied on a sustained basis can increase the most self-determined types of motivation, intrinsic motivation and identified regulation, in secondary education students. Students’ perceptions after experiencing Cooperative Learning for a long period of time reflected four positive ideas: cooperation, relatedness, enjoyment and novelty and a negative one: disappointment. Both the positive and the negative ideas should be considered when implementing Cooperative Learning in physical education, because students experience them.Keywords: physical educationsecondary educationmodels-based learning Disclosure statementNo potential conflict of interest was reported by the authors.ORCIDJavier Fernandez-Rio http://orcid.org/0000-0002-1368-3723

BACKGROUND: Dying at home and dying at the preferred place of death are advocated to be desirable outcomes of palliative care. More insight is needed in their usefulness as quality indicators. Our objective is to describe whether "the percentage of patients dying at home" and "the percentage of patients who died in their place of preference" are feasible and informative quality indicators. METHODS AND FINDINGS: A mortality follow-back study was conducted, based on data recorded by representative GP networks regarding home-dwelling patients who died non-suddenly in Belgium (n = 1036), The Netherlands (n = 512), Italy (n = 1639) or Spain (n = 565). "The percentage of patients dying at home" ranged between 35.3% (Belgium) and 50.6% (The Netherlands) in the four countries, while "the percentage of patients dying at their preferred place of death" ranged between 67.8% (Italy) and 86.0% (Spain). Both indicators were strongly associated with palliative care provision by the GP (odds ratios of 1.55-13.23 and 2.30-6.63, respectively). The quality indicator concerning the preferred place of death offers a broader view than the indicator concerning home deaths, as it takes into account all preferences met in all locations. However, GPs did not know the preferences for place of death in 39.6% (The Netherlands) to 70.3% (Italy), whereas the actual place of death was known in almost all cases. CONCLUSION: GPs know their patients' actual place of death, making the percentage of home deaths a feasible indicator for collection by GPs. However, patients' preferred place of death was often unknown to the GP. We therefore recommend using information from relatives as long as information from GPs on the preferred place of death is lacking. Timely communication about the place where patients want to be cared for at the end of life remains a challenge for GPs.

We evaluated the prevalence of hepatitis E virus (HEV) in the pork production chain in Czech Republic, Italy, and Spain during 2010. A total of 337 fecal, liver, and meat samples from animals at slaughterhouses were tested for HEV by real-time quantitative PCR. Overall, HEV was higher in Italy (53%) and Spain (39%) than in Czech Republic (7.5%). HEV was detected most frequently in feces in Italy (41%) and Spain (39%) and in liver (5%) and meat (2.5%) in Czech Republic. Of 313 sausages sampled at processing and point of sale, HEV was detected only in Spain (6%). HEV sequencing confirmed only g3 HEV strains. Indicator virus (porcine adenovirus) was ubiquitous in fecal samples and absent in liver samples and was detected in 1 slaughterhouse meat sample. At point of sale, we found porcine adenovirus in sausages (1%-2%). The possible dissemination of HEV and other fecal viruses through pork production demands containment measures.

This study aimed to gain an insight into the adaptations of muscle strength and skeletal muscle thickness after two different volumes of blood flow restriction training (BFRT), and compare them with high-intensity training. The sample was divided into four groups: low-volume, low-intensity BFRT (BFRT LV); high-volume, low-intensity BFRT (BFRT HV); traditional high-intensity resistance training (HIT); and a control group, which maintained their routine activities (CON). Leg extension one repetition maximum (1RM), isokinetic peak knee extension, and flexion torques at 60°/s and 180°/s as well as muscle thickness of the rectus femoris (RF) and vastus lateralis (VL) were assessed at baseline and after 5 weeks of training BFRT LV (7.03%, P < 0.05), BFRT HV (6.24%, P < 0.05) and HIT (18.86%, P < 0.001) groups increased 1RM performance, while no changes were observed in the CON group. Muscle thickness of the RF and VL was increased irrespective of the training group (7.5%, P < 0.001; and 9.9%, P < 0.001, respectively). We conclude that doubling the exercise volume with BFRT causes no further benefit with muscular size or strength. Although similar increases in muscle thickness were observed between training groups, HIT increased 1RM performance to a greater extent compared to either volume of BFRT.

Pandemic H1N1 influenza A (H1N1pdm) is currently a dominant circulating influenza strain worldwide. Severe cases of H1N1pdm infection are characterized by prolonged activation of the immune response, yet the specific role of inflammatory mediators in disease is poorly understood. The inflammatory cytokine IL-6 has been implicated in both seasonal and severe pandemic H1N1 influenza A (H1N1pdm) infection. Here, we investigated the role of IL-6 in severe H1N1pdm infection. We found IL-6 to be an important feature of the host response in both humans and mice infected with H1N1pdm. Elevated levels of IL-6 were associated with severe disease in patients hospitalized with H1N1pdm infection. Notably, serum IL-6 levels associated strongly with the requirement of critical care admission and were predictive of fatal outcome. In C57BL/6J, BALB/cJ, and B6129SF2/J mice, infection with A/Mexico/4108/2009 (H1N1pdm) consistently triggered severe disease and increased IL-6 levels in both lung and serum. Furthermore, in our lethal C57BL/6J mouse model of H1N1pdm infection, global gene expression analysis indicated a pronounced IL-6 associated inflammatory response. Subsequently, we examined disease and outcome in IL-6 deficient mice infected with H1N1pdm. No significant differences in survival, weight loss, viral load, or pathology were observed between IL-6 deficient and wild-type mice following infection. Taken together, our findings suggest IL-6 may be a potential disease severity biomarker, but may not be a suitable therapeutic target in cases of severe H1N1pdm infection due to our mouse data.