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IntroductionAssessment of left ventricular ejection fraction (LVEF) is one of the primary objectives of echocardiography. The gold standard assessment technique in emergency medicine is eyeballing. A new tool is now available on pocket ultrasound devices (PUD): automatic LVEF. The primary aim of this study was to evaluate the concordance between LVEF values estimated by automatic LVEF with PUD and by cardiac magnetic resonance imaging (MRI).MaterialsThis was a prospective, monocentric, and observational study. All adult patients with an indication for cardiac MRI underwent a point-of-care ultrasound. Blinded to the MRI results, the emergency physician assessed LVEF using the automatic PUD tool and by visual evaluation.ResultsSixty patients were included and analyzed. Visual estimation of LVEF was feasible for all patients and automatic evaluation for 52 (87%) patients. Lin's concordance correlation coefficient between automatic ejection fraction with PUD and by cardiac MRI was 0.23 (95% CI, 0.03-0.40).ConclusionConcordance between LVEF estimated by the automatic ejection fraction with PUD and LVEF estimated by MRI was non-existent.

Human Papillomavirus (HPV) prophylactic vaccination has proven effective in preventing new infections, but it does not treat existing HPV infections or associated diseases. Hence, there is still an important reservoir of HPV in adults, as vaccination programs are mainly focused on young women. The primary objective of this non-randomized, open-label trial is to evaluate if a 3-dose regimen of Gardasil-9 in HPV16/18-positive women could reduce the infective capacity of their body fluids. We aim to assess if vaccine-induced antibodies could neutralize virions present in the mucosa, thus preventing the release of infective particles and HPV transmission to sexual partners. As our main endpoint, the E1^E4-HaCaT model will be used to assess the infectivity rate of cervical, anal and oral samples, obtained from women before and after vaccination. HPV DNA positivity, virion production, seroconversion, and the presence of antibodies in the exudates, will be evaluated to attribute infectivity reduction to vaccination. Our study will recruit two different cohorts (RIFT-HPV1 and RIFT-HPV2) of non-vaccinated adult women. RIFT-HPV1 will include subjects with an HPV16/18 positive cervical test and no apparent cervical lesions or cervical lesions eligible for conservative treatment. RIFT-HPV2 will include subjects with an HPV16/18 positive anal test and no apparent anal lesions or anal lesions eligible for conservative treatment, as well as women with an HPV16/18 positive cervical test and HPV-associated vulvar lesions. Subjects complying with inclusion criteria for both cohorts will be recruited to the main cohort, RIFT-HPV1. Three doses of Gardasil-9 will be administered intramuscularly at visit 1 (0 months), visit 2 (2 months) and visit 3 (6 months). Even though prophylactic HPV vaccines would not eliminate a pre-existing infection, our results will determine if HPV vaccination could be considered as a new complementary strategy to prevent HPV-associated diseases by reducing viral spread. Trial registration: https://clinicaltrials.gov/ct2/show/NCT05334706.

Introduction: Assessment of left ventricular ejection fraction (LVEF) is one of the primary objectives of echocardiography. The gold standard assessment technique in emergency medicine is eyeballing. A new tool is now available on pocket ultrasound devices (PUD): automatic LVEF. The primary aim of this study was to evaluate the concordance between LVEF values estimated by automatic LVEF with PUD and by cardiac magnetic resonance imaging (MRI). Materials: This was a prospective, monocentric, and observational study. All adult patients with an indication for cardiac MRI underwent a point-of-care ultrasound. Blinded to the MRI results, the emergency physician assessed LVEF using the automatic PUD tool and by visual evaluation. Results: Sixty patients were included and analyzed. Visual estimation of LVEF was feasible for all patients and automatic evaluation for 52 (87%) patients. Lin's concordance correlation coefficient between automatic ejection fraction with PUD and by cardiac MRI was 0.23 (95% CI, 0.03–0.40). Conclusion: Concordance between LVEF estimated by the automatic ejection fraction with PUD and LVEF estimated by MRI was non-existent. [ABSTRACT FROM AUTHOR]

Introduction Breast and prostate cancer survivors can experience impaired quality of life (QoL) in several QoL domains. The current strategy to support cancer survivors with impaired QoL is suboptimal, leading to unmet patient needs. ASCAPE aims to provide personalized- and artificial intelligence (AI)-based predictions for QoL issues in breast- and prostate cancer patients as well as to suggest potential interventions to their physicians to offer a more modern and holistic approach on cancer rehabilitation. Methods and analyses An AI-based platform aiming to predict QoL issues and suggest appropriate interventions to clinicians will be built based on patient data gathered through medical records, questionnaires, apps, and wearables. This platform will be prospectively evaluated through a longitudinal study where breast and prostate cancer survivors from four different study sites across the Europe will be enrolled. The evaluation of the AI-based follow-up strategy through the ASCAPE platform will be based on patients’ experience, engagement, and potential improvement in QoL during the study as well as on clinicians’ view on how ASCAPE platform impacts their clinical practice and doctor-patient relationship, and their experience in using the platform. Ethics and dissemination ASCAPE is the first research project that will prospectively investigate an AI-based approach for an individualized follow-up strategy for patients with breast- or prostate cancer focusing on patients’ QoL issues. ASCAPE represents a paradigm shift both in terms of a more individualized approach for follow-up based on QoL issues, which is an unmet need for cancer survivors, and in terms of how to use Big Data in cancer care through democratizing the knowledge and the access to AI and Big Data related innovations. Trial registration Trial Registration on clinicaltrials.gov: NCT04879563.

Neurodegenerative diseases, such as Parkinson’s disease, are heterogeneous disorders with a multifactorial nature involving impaired bioenergetics. Stem-regenerative medicine and bioenergetics have been proposed as promising therapeutic targets in the neurologic field. The rationale of the present study was to assess the potential of human-derived adipose stem cells (hASCs) to transdifferentiate into neuronal-like cells (NhASCs and neurospheres) and explore the hASC bioenergetic profile. hASC neuronal transdifferentiation was performed through neurobasal media and differentiation factor exposure. High resolution respirometry was assessed. Increased MAP-2 neuronal marker protein expression upon neuronal induction (p

PurposeMany rural American Indian and Alaska Native (AIAN) veterans receive care from the Indian Health Service (IHS). United States Department of Veterans Affairs (VA) has reimbursement agreements with some IHS facilities and tribal programs and seeks to expand community partnerships in tribal areas, but details of how AIAN veterans use IHS are unknown. We aimed to assess the health status, service utilization patterns, and cost of care of veterans who use IHS.MethodsWe used comprehensive and integrated IHS data to compare health status, health service utilization and treatment cost of veterans (n = 12,242) to a matched sample of non-veterans (n = 12,242). We employed logistic, linear, or negative binomial regressions as appropriate, by sex and overall.FindingsCompared to non-veterans, veterans had lower odds of having hypertension, renal disease, all-cause dementia, and alcohol or drug use disorders, but had similar burden of other conditions. In service utilization, veterans had lower hospital inpatient days; patterns were mixed across outpatient services. Unadjusted treatment costs for veterans and non-veterans were $3,923 and $4,145, respectively; veteran adjusted treatment costs were statistically lower. Differences in significance by sex were found for health conditions and service use.ConclusionsAIAN veterans, compared to AIAN non-veterans, were not less healthy, nor did they require more intensive or more costly care under IHS. Our results indicate the viability and importance of expanding IHS-VA partnerships in community care.

The excellent preservation of the waterlogged botanical remains of the multiphase Neolithic pile-dwelling site of Zug-Riedmatt (Central Switzerland) yielded an ideal dataset to delve into the issue of plant economy of a community spanning several decades. The study identified a major change in crops where oil plants played a key role in the site's initial phase before being supplanted over the course of a few decades by naked wheat, barley and pea. Wild plants continued to be gathered albeit in different proportions. In the latest settlement phase, the changes in the local vegetation and in the values of the analyses of carbon stable isotopes suggest a less humid environment. The hypothesis is that the changes perceived in the plant economy represent a resilience strategy adopted by the inhabitants in reaction to short term local climatic alterations. The two types of soil sampling techniques (monolith and bulk) allowed comparing these results. While the density of plant remains appears to be underestimated among the samples collected by the monolith technique, the proportions of economic taxa remain unaffected. The findings thus reveal that when the bulk samplings are distributed carefully throughout multiphase sites and avoid mixing stratigraphical units, and if the samplings are representative of all archaeological features from a whole area, then each of the two techniques offer analogous results.

BackgroundThe Global Trigger Tool (GTT) has become a worldwide used method for estimating adverse events through a retrospective patient record review. However, little is known about the facilitators and the challenges in the GTT-implementation process. Thus, this study followed two aims: First, to apply a comprehensive set of feasibility criteria to qualitatively and systematically assess the GTT-implementation process in three departments of German university hospitals. Second, to identify the facilitators and the obstacles met in the GTT-implementation process and to derive recommendations for supporting other hospitals in implementing the GTT in clinical practice.MethodsThe study used a qualitative documentary method based on process documentation, with written and verbal feedback from the reviewer, as well as evaluating the study sites during the implementation process. The study was conducted in three departments, each in a different German university hospital. The authors applied a comprehensive set of 22 feasibility criteria assessing the level of challenge in GTT implementation. The results were synthesized and they focused on the facilitators and the challenges.ResultsOf these 22 feasibility criteria, nine were assessed as a low-level challenge, eleven regarded as a moderate-level challenge, and two with a problematic level of challenge. In particular, the lack of time and staff resources, the quality of the information in the patient records, organizational procedures, and local issues, posed major challenges in the implementation process. By contrast, the use of local coordinators and an external expert made important contributions to the GTT implementation.ConclusionsConsidering the facilitators and the obstacles beforehand may help with the implementation of the GTT in routine practice. In particular, early and effective planning can reduce or prevent critical challenges in terms of time, staff resources, and organizational aspects.

The aim of this study was to determine reference intervals in an outpatient population from Vall d'Hebron laboratory using an indirect approach previously described in a Dutch population (NUMBER project). We used anonymized test results from individuals visiting general practitioners and analysed during 2018. Analytical quality was assured by EQA performance, daily average monitoring and by assessing longitudinal accuracy between 2018 and 2020 (using trueness verifiers from Dutch EQA). Per test, outliers by biochemically related tests were excluded, data were transformed to a normal distribution (if necessary) and means and standard deviations were calculated, stratified by age and sex. In addition, the reference limit estimator method was also used to calculate reference intervals using the same dataset. Finally, for standardized tests reference intervals obtained were compared with the published NUMBER results. Reference intervals were calculated using data from 509,408 clinical requests. For biochemical tests following a normal distribution, similar reference intervals were found between Vall d'Hebron and the Dutch study. For creatinine and urea, reference intervals increased with age in both populations. The upper limits of Gamma-glutamyl transferase were markedly higher in the Dutch study compared to Vall d'Hebron results. Creatine kinase and uric acid reference intervals were higher in both populations compared to conventional reference intervals. Medical test results following a normal distribution showed comparable and consistent reference intervals between studies. Therefore a simple indirect method is a feasible and cost-efficient approach for calculating reference intervals. Yet, for generating standardized calculated reference intervals that are traceable to higher order materials and methods, efforts should also focus on test standardization and bias assessment using commutable trueness verifiers.

Development of in vivo daptomycin resistance (DAP-R) among Staphylococcus aureus clinical isolates, in association with clinical treatment failures, has become a major therapeutic problem. This issue is especially relevant to methicillin-resistant S. aureus (MRSA) strains in the context of invasive endovascular infections. In the current study, we used three well-characterized and clinically-derived DAP-susceptible (DAP-S) vs. resistant (DAP-R) MRSA strain-pairs to elucidate potential genotypic mechanisms of the DAP-R phenotype. In comparison to the DAP-S parental strains, DAP-R isolates demonstrated (i) altered expression of two key determinants of net positive surface charge, either during exponential or stationary growth phases (i.e., dysregulation of dltA and mprF), (ii) a significant increase in the D-alanylated wall teichoic acid (WTA) content in DAP-R strains, reflecting DltA gain-in-function; (iii) heightened elaboration of lysinylated-phosphatidylglyderol (L-PG) in DAP-R strains, reflecting MprF gain-in-function; (iv) increased cell membrane (CM) fluidity, and (v) significantly reduced susceptibility to prototypic cationic host defense peptides of platelet and leukocyte origins. In the tested DAP-R strains, genes conferring positive surface charge were dysregulated, and their functionality altered. However, there were no correlations between relative surface positive charge or cell wall thickness and the observed DAP-R phenotype. Thus, charge repulsion mechanisms via altered surface charge may not be sufficient to explain the DAP-R outcome. Instead, changes in the compositional or biophysical order of the DAP CM target of such DAP-R strains (i.e., increased fluidity) may be essential to this phenotype. Taken together, DAP-R in S. aureus appears to involve multi-factorial and strain-specific adaptive mechanisms.

Human Papillomavirus (HPV) prophylactic vaccination has proven effective in preventing new infections, but it does not treat existing HPV infections or associated diseases. Hence, there is still an important reservoir of HPV in adults, as vaccination programs are mainly focused on young women. The primary objective of this non-randomized, open-label trial is to evaluate if a 3-dose regimen of Gardasil-9 in HPV16/18-positive women could reduce the infective capacity of their body fluids. We aim to assess if vaccine-induced antibodies could neutralize virions present in the mucosa, thus preventing the release of infective particles and HPV transmission to sexual partners. As our main endpoint, the E1^E4-HaCaT model will be used to assess the infectivity rate of cervical, anal and oral samples, obtained from women before and after vaccination. HPV DNA positivity, virion production, seroconversion, and the presence of antibodies in the exudates, will be evaluated to attribute infectivity reduction to vaccination. Our study will recruit two different cohorts (RIFT-HPV1 and RIFT-HPV2) of non-vaccinated adult women. RIFT-HPV1 will include subjects with an HPV16/18 positive cervical test and no apparent cervical lesions or cervical lesions eligible for conservative treatment. RIFT-HPV2 will include subjects with an HPV16/18 positive anal test and no apparent anal lesions or anal lesions eligible for conservative treatment, as well as women with an HPV16/18 positive cervical test and HPV-associated vulvar lesions. Subjects complying with inclusion criteria for both cohorts will be recruited to the main cohort, RIFT-HPV1. Three doses of Gardasil-9 will be administered intramuscularly at visit 1 (0 months), visit 2 (2 months) and visit 3 (6 months). Even though prophylactic HPV vaccines would not eliminate a pre-existing infection, our results will determine if HPV vaccination could be considered as a new complementary strategy to prevent HPV-associated diseases by reducing viral spread. Trial registration: https://clinicaltrials.gov/ct2/show/NCT05334706. [ABSTRACT FROM AUTHOR]

BackgroundContact tracing is an important tool for suppressing COVID-19 but has been difficult to adapt to the conditions of a public health emergency. This study explored the experiences and perspectives of volunteer contact tracers in order to identify facilitators, challenges, and novel solutions for implementing COVID-19 contact tracing.MethodsAs part of a study to evaluate an emergently established volunteer contact tracing program for COVID-19 in New Haven, Connecticut, April-June 2020, we conducted focus groups with 36 volunteer contact tracers, thematically analyzed the data, and synthesized the findings using the RE-AIM implementation framework.ResultsTo successfully reach cases and contacts, participants recommended identifying clients' outreach preferences, engaging clients authentically, and addressing sources of mistrust. Participants felt that the effectiveness of successful isolation and quarantine was contingent on minimizing delays in reaching clients and on systematically assessing and addressing their nutritional, financial, and housing needs. They felt that successful adoption of a volunteer-driven contact tracing model depended on the ability to recruit self-motivated contact tracers and provide rapid training and consistent, supportive supervision. Participants noted that implementation could be enhanced with better management tools, such as more engaging interview scripts, user-friendly data management software, and protocols for special situations and populations. They also emphasized the value of coordinating outreach efforts with other involved providers and agencies. Finally, they believed that long-term maintenance of a volunteer-driven program requires monetary or educational incentives to sustain participation.ConclusionsThis is one of the first studies to qualitatively examine implementation of a volunteer-run COVID-19 contact tracing program. Participants identified facilitators, barriers, and potential solutions for improving implementation of COVID-19 contact tracing in this context. These included standardized communication skills training, supportive supervision, and peer networking to improve implementation, as well as greater cooperation with outside agencies, flexible scheduling, and volunteer incentives to promote sustainability.

Background Multiple sclerosis (MS) is the most common autoimmune inflammatory disease of the central nervous system in Europe, often causing severe physical, cognitive and emotional impairments. Currently, it is unclear whether the healthcare provisions of people with MS (PwMS) are in line with the recommendations for treatment based on guidelines or patients’ needs. The main objectives of the study are as follows: (a) to investigate how well PwMS are treated; and (b) to develop a needs-oriented, patient-centred care model. Methods This mixed-methods study focuses on adult PwMS living in Lower Saxony, a federal state in Germany. The qualitative study comprises focus groups with PwMS, physicians and people involved in the healthcare process as well as a future workshop. The quantitative study comprises a cross-sectional online survey and addresses the patient-relevant outcomes and needs, as previously determined by literature searches and focus groups. It will be administered to all PwMS who are insured by the statutory health insurance company involved in the project (n~7,000). The survey data will be linked to the longitudinal secondary data from the statutory health insurance company and data from the German MS registry where available. The linked and single data sources will be statistically analysed. Discussion By comprehensively comparing the current healthcare provisions with the needs and requirements of PwMS, the strengths and weaknesses of the overall healthcare process and provision of assistive devices can be identified. The barriers and facilitators of the health service providers and their impact on daily life will be explored (qualitative analyses). Reliable recommendations for improvements will be given based on a study population drawn from the largest statutory health insurance company in Lower Saxony (quantitative analyses). However, the inherent advantages and limitations of the qualitative and quantitative research approaches need to be considered. Trial registration The study is registered at German Clinical Trials Register DRKS00021741.

Chiari Malformation Type 1 (CM-1) is characterized by herniation of the cerebellar tonsils below the foramen magnum and the presence of headaches and other neurologic symptoms. Cranial bone constriction is suspected to be the most common biologic mechanism leading to CM-1. However, other mechanisms may also contribute, particularly in the presence of connective tissue disorders (CTDs), such as Ehlers Danlos Syndrome (EDS). Accumulating data suggest CM-1 with connective tissue disorders (CTD+) may have a different patho-mechanism and different genetic risk factors than CM-1 without CTDs (CTD-). To identify CM-1 genetic risk variants, we performed whole exome sequencing on a single large, multiplex family from Spain and targeted sequencing on a cohort of 186 unrelated adult, Caucasian females with CM-1. Targeted sequencing captured the coding regions of 21 CM-1 and EDS candidate genes, including two genes identified in the Spanish family. Using gene burden analysis, we compared the frequency of rare, functional variants detected in CM-1 cases versus publically available ethnically-matched controls from gnomAD. A secondary analysis compared the presence of rare variants in these genes between CTD+ and CTD- CM-1 cases. In the Spanish family, rare variants co-segregated with CM-1 in COL6A5, ADGRB3 and DST. A variant in COL7A1 was present in affected and unaffected family members. In the targeted sequencing analysis, rare variants in six genes (COL7A1, COL5A2, COL6A5, COL1A2, VEGFB, FLT1) were significantly more frequent in CM-1 cases compared to public controls. In total, 47% of CM-1 cases presented with rare variants in at least one of the four significant collagen genes and 10% of cases harbored variants in multiple significant collagen genes. Moreover, 26% of CM-1 cases presented with rare variants in the COL6A5 gene. We also identified two genes (COL7A1, COL3A1) for which the burden of rare variants differed significantly between CTD+ and CTD- CM-1 cases. A higher percentage of CTD+ patients had variants in COL7A1 compared to CTD+ patients, while CTD+ patients had fewer rare variants in COL3A1 than did CTD- patients. In summary, rare variants in several collagen genes are particularly frequent in CM-1 cases and those in COL6A5 co-segregated with CM-1 in a Spanish multiplex family. COL6A5 has been previously associated with musculoskeletal phenotypes, but this is the first association with CM-1. Our findings underscore the contribution of rare genetic variants in collagen genes to CM-1, and suggest that CM-1 in the presence and absence of CTD symptoms is driven by different genes.

Africa is home to some of the world's most functionally diverse guilds of large carnivores. However, they are increasingly under threat from anthropogenic pressures that may exacerbate already intense intra-guild competition. Understanding the coexistence mechanisms employed by these species in human-impacted landscapes could help shed light on some of the more subtle ways in which humans may impact wildlife populations, and inform multi-species conservation planning. We used camera trap data from Tanzania's Ruaha-Rungwa landscape to explore temporal and spatiotemporal associations between members of an intact East African large carnivore guild, and determine how these varied across gradients of anthropogenic impact and protection. All large carnivores except African wild dog (Lycaon pictus) exhibited predominantly nocturnal road-travel behaviour. Leopard (Panthera pardus) appeared to employ minor temporal avoidance of lion (Panthera leo) in all sites except those where human impacts were highest, suggesting that leopard may have been freed up from avoidance of lion in areas where the dominant competitor was less abundant, or that the need for leopard to avoid humans outweighed the need to avoid sympatric competitors. Lion appeared to modify their activity patterns to avoid humans in the most impacted areas. We also found evidence of avoidance and attraction among large carnivores: lion and spotted hyaena (Crocuta crocuta) followed leopard; leopard avoided lion; spotted hyaena followed lion; and lion avoided spotted hyaena. Our findings suggest that large carnivores in Ruaha-Rungwa employ fine-scale partitioning mechanisms to facilitate coexistence with both sympatric species and humans, and that growing human pressures may interfere with these behaviours.

[This corrects the article DOI: 10.1371/journal.pone.0212028.].

INTRODUCTION:Periodontitis is associated with increased serum lipopolysaccharide (LPS) activity, which may be one mechanism linking periodontitis with the risk of cardiovascular diseases. As LPS-carrying proteins including lipoproteins modify LPS-activity, we investigated the determinants of serum LPS-neutralizing capacity (LPS-NC) in ischemic stroke. The association of LPS-NC and Aggregatibacter actinomycetemcomitans, a major microbial biomarker in periodontitis, was also investigated. MATERIALS AND METHODS:The assay to measure LPS-NC was set up by spiking serum samples with E. coli LPS. The LPS-NC, LPS-binding protein (LBP), soluble CD14 (sCD14), lipoprotein profiles, apo(lipoprotein) A-I, apoB, and phospholipid transfer protein (PLTP) activity, were determined in 98 ischemic stroke patients and 100 age- and sex-matched controls. Serum and saliva immune response to A. actinomycetemcomitans, its concentration in saliva, and serotype-distribution were examined. RESULTS:LPS-NC values ranged between 51-83% in the whole population. Although several of the LPS-NC determinants differed significantly between cases and controls (PLTP, sCD14, apoA-I, HDL-cholesterol), the levels did not (p = 0.056). The main determinants of LPS-NC were i) triglycerides (β = -0.68, p

Patients with multimorbidity and complex health care needs are usually vulnerable elders with several concomitant advanced chronic diseases. Our research aim was to evaluate differences in patterns of multimorbidity by gender in this population and their possible prognostic implications, measured as in-hospital mortality, 1-month readmissions, and 1-year mortality. We focused on a cohort of elderly patients with well-established multimorbidity criteria admitted to a specific unit for chronic complex-care patients. Multimorbidity criteria, the Charlson, PROFUND and Barthel indexes, and the Pfeiffer test were collected prospectively during their stays. A total of 843 patients (49.2% men) were included, with a median age of 84 [interquartile range (IQR) 79-89] years. The women were older, with greater functional dependence [Barthel index: 40 (IQR:10-65) vs. 60 (IQR: 25-90)], showed more cognitive deterioration [Pfeiffer test: 5 (IQR:1-9) vs. 1 (0-6)], and had worse scores on the PROFUND index [15 (IQR:9-18) vs. 11.5 (IQR: 6-15)], all p

The target species (Aphia minuta and Pseudaphya ferreri) of the transparent goby fishery on Mallorca Island (Balearic Islands, western Mediterranean) are currently discarded when the maximum daily catch is exceeded or when the sorting process is unworkable. The mortality suffered by this discarded fraction remains unknown, although it may be important for resource management. Accordingly, the aims of this study were to (1) assess the environmental drivers of the relative post-release survival of the discarded target species and (2) test the correlations between post-release survival and two behavior-related variables (swimming speed and its increase after a stimulus, assessed via video recording). To do so, mortality of the target species from 47 hauls sampled under normal fishing boat operations was monitored when the gear was onboard and after a few hours. At the reference level (an average depth of 25.7 m and temperature of 15.7 ºC), the immediate survival was 99.9% (95% CI: 97.9 to 100%), but the estimated post-release survival decreased to 47.2% (33.8 to 65.8%). Relative post-release mortality doubled when the water temperature increased by 2.8 ºC or when the fishing depth increased up to 32 m. Furthermore, the swimming speed of the target species was significantly correlated with the estimated post-release survival; thus, this vitality metric may offer a promising strategy for more easily estimating post-release mortality in other fisheries.

Our knowledge about the structure and function of Andean forests at regional scales remains limited. Current initiatives to study forests over continental or global scales still have important geographical gaps, particularly in regions such as the tropical and subtropical Andes. In this study, we assessed patterns of structure and tree species diversity along ~ 4000 km of latitude and ~ 4000 m of elevation range in Andean forests. We used the Andean Forest Network (Red de Bosques Andinos, https://redbosques.condesan.org/) database which, at present, includes 491 forest plots (totaling 156.3 ha, ranging from 0.01 to 6 ha) representing a total of 86,964 identified tree stems ≥ 10 cm diameter at breast height belonging to 2341 identified species, 584 genera and 133 botanical families. Tree stem density and basal area increases with elevation while species richness decreases. Stem density and species richness both decrease with latitude. Subtropical forests have distinct tree species composition compared to those in the tropical region. In addition, floristic similarity of subtropical plots is between 13 to 16% while similarity between tropical forest plots is between 3% to 9%. Overall, plots ~ 0.5-ha or larger may be preferred for describing patterns at regional scales in order to avoid plot size effects. We highlight the need to promote collaboration and capacity building among researchers in the Andean region (i.e., South-South cooperation) in order to generate and synthesize information at regional scale.

ObjectiveAdolescent migrants present psychological disorders more frequently than the corresponding host population but their access to care and to follow-up are less effective. The French method of transcultural psychotherapy (TPT) was conceived to respond to these problems. Our objective is to assess how these adolescents and their families perceive the experience and effectiveness of TPT.MethodWe conducted semistructured interviews with the families of adolescents seen for TPT. The data were analyzed by a qualitative thematic methodology.ResultsWe spoke to 21 participants in 8 families. The families came to TPT with a sense that the teen's current treatment was at an impasse. During the follow-up, they noted that family communication and relationships had improved, as had their connection to their culture of origin. Besides commenting on what they perceived as limitations, families identified specific elements of TPT as therapeutic.ConclusionThe pronounced diversity of the group and the use of both multiperspective narration and an interpreter were specific elements driving the construction of a good therapeutic alliance, despite the initial barriers. Pursuit of the evaluation of TPT is essential to advance the psychiatric care of adolescent migrants.

ObjectivesTo identify factors associated with hospital admission and mortality within the first 30 days after enrolment in an outpatient parenteral antimicrobial therapy (OPAT) program, also analysing adequacy of the treatment regimen and clinical outcomes.Patients and methodsThis was a retrospective cohort study conducted between October 2016 and June 2017 in the state of São Paulo, Brazil. Variables related to hospital admission and mortality were subjected to bivariate analysis, and those with a PResultsWe evaluated 276 patients, of whom 80.5% were ≥60 years of age and 69.9% had more than one comorbidity. Of the patients evaluated, 41.3% had pneumonia and 35.1% had a urinary tract infection. The most common etiological agent, isolated in 18 (31.6%) cases, was Klebsiella pneumoniae, and 13 (72,2%) strains were carbapenem resistant. The OPAT was in accordance with the culture results in 76.6% of the cases and with the institutional protocols in 76.4%. The majority (64.5%) of the patients were not admitted, and a cure or clinical improvement was achieved in 78.6%. Multivariate analysis showed that, within the first 30 days after enrolment, the absence of a physician office visit was a predictor of hospital admission (PConclusionsThis study demonstrated the viability of OPAT in elderly patients with pulmonary or urinary tract infections in an area with a high prevalence of multidrug-resistant bacteria and that a post-discharge physician office visit is protective against hospital admission and mortality.

Ivermectin has recently shown efficacy against SARS-CoV-2 in-vitro. We retrospectively reviewed severe COVID-19 patients receiving standard doses of ivermectin and we compared clinical and microbiological outcomes with a similar group of patients not receiving ivermectin. No differences were found between groups. We recommend the evaluation of high-doses of ivermectin in randomized trials against SARS-CoV-2.

Spirometry remains essential for the diagnosis of airway obstruction. Nevertheless, its performance in elderly hospitalized patients with multimorbidity can be difficult. The aim of this study is to assess the utility of the COPD-6 portable device in this population. We included all patients hospitalized for exacerbation of chronic diseases in a medical ward specialized in the care of multimorbidity patients, between September 2017 and May 2018. A questionnaire including sociodemographic, cognitive and functional impairment, among other variables, was completed the last day of admission. Subsequently, patients attempted to perform three valid respiratory manoeuvres with the COPD-6 device and then conventional spirometry. A total of 184 patients were included (mean age of 79.61 years, 55% men). Forty-seven (25.54%) patients were able to perform complete spirometric manoeuvres and 99 (53.8%) could perform a valid FEV1/FEV6 determination. The inability to perform a valid spirometry was related with the patient's age, functional physical disability, cognitive impairment or the presence of delirium or dysphagia during admission. Only 9% of patients with a Mini Mental Cognitive Examination (MMEC) lower than 24 points could perform a valid spirometry. Of the patients with an MMEC < 24 points and unable to perform spirometry, 34% were able to complete the FEV1/FEV6 manoeuvres. No differences were found in the Charlson index, multimorbidity scale, number of domiciliary drugs, or length of stay between those patients able and those not able to perform respiratory manoeuvres. The agreement between the values for FEV1 measured with COPD-6 and those observed in the spirometry was good (r: 0.71; p

Since biotechnological research becomes more and more important for industrial applications, there is an increasing need for scalable and controllable laboratory procedures. A widely used approach in biotechnological research to improve the performance of a process is to vary the growth rates in order to find the right balance between growth and the production. This can be achieved by the application of a suitable feeding strategy. During this initial bioprocess development, it is beneficial to have at hand cheap and easy setups that work in parallel (e.g. in shaking flasks). Unfortunately, there is a gap between these easy setups and defined and controllable processes, which are necessary for up-scaling to an industrial relevant volume. One prerequisite to test and evaluate different process strategies apart from batch-mode is the availability of pump systems that allow for defined feeding profiles in shaking flasks. To our knowledge, there is no suitable dosing device on the market which fulfils the requirements of being cheap, precise, programmable, and parallelizable. Commercially available dosing units are either already integrated in bioreactors and therefore inflexible, or not programmable, or expensive, or a combination of those. Here, we present a LEGO-MINDSTORMS-based syringe pump, which has the potential of being widely used in daily laboratory routine due to its low price, programmability, and parallelisability. The acquisition costs do not exceed 350 € for up to four dosing units, that are independently controllable with one EV3 block. The system covers flow rates ranging from 0.7 μL min-1 up to 210 mL min-1 with a reliable flux. One dosing unit can convey at maximum a volume of 20 mL (using all 4 units even up to 80 mL in total) over the whole process time. The design of the dosing unit enables the user to perform experiments with up to four different growth rates in parallel (each measured in triplicates) per EV3-block used. We estimate, that the LEGO-MINDSTORMS-based dosing unit with 12 syringes in parallel is reducing the costs up to 50-fold compared to a trivial version of a commercial pump system (~1500 €) which fits the same requirements. Using the pump, we set the growth rates of a E. coli HMS174/DE3 culture to values between 0.1 and 0.4 h-1 with a standard deviation of at best 0.35% and an average discrepancy of 13.2%. Additionally, we determined the energy demand of a culture for the maintenance of the pTRA-51hd plasmid by quantifying the changes in biomass yield with different growth rates set. Around 25% of total substrate taken up is used for plasmid maintenance. To present possible applications and show the flexibility of the system, we applied a constant feed to perform microencapsulation of Pseudomonas putida and an individual dosing profile for the purification of a his-tagged eGFP via IMAC. This smart and versatile dosing unit, which is ready-to-use without any prior knowledge in electronics and control, is affordable for everyone and due to its flexibility and broad application range a valuable addition to the laboratory routine.

Clinical and model studies indicate that low nitric oxide (NO) bioavailability due in part to profound hypoargininemia contributes to cerebral malaria (CM) pathogenesis. Protection against CM pathogenesis may be achieved by altering the diet before infection with Plasmodium falciparum infection (nutraceutical) or by administering adjunctive therapy that decreases CM mortality (adjunctive therapy). This hypothesis was tested by administering citrulline or arginine in experimental CM (eCM). We report that citrulline injected as prophylaxis immediately post infection (PI) protected virtually all mice by ameliorating (i) hypoargininemia, (ii) urea cycle impairment, and (iii) disruption of blood brain barrier. Citrulline prophylaxis inhibited plasma arginase activity. Parasitemia was similar in citrulline- and vehicle control-groups, indicating that protection from pathogenesis was not due to decreased parasitemia. Both citrulline and arginine administered from day 1 PI in the drinking water significantly protected mice from eCM. These observations collectively indicate that increasing dietary citrulline or arginine decreases eCM mortality. Citrulline injected ip on day 4 PI with quinine-injected ip on day 6 PI partially protected mice from eCM; citrulline plus scavenging of superoxide with pegylated superoxide dismutase and pegylated catalase protected all recipients from eCM. These findings indicate that ameliorating hypoargininemia with citrulline plus superoxide scavenging decreases eCM mortality.

Noble pen shell or fan mussel, Pinna nobilis Linnaeus (1758), protected since 1992, was incorporated into the Spanish Catalogue of Threatened Species (Category: Vulnerable, Royal Decree 139/2011). The status is presently in the process of being catalogued as critically endangered, pending approval by Spanish Government (https://www.mapama.gob.es/es/biodiversidad/participacion-publica/Borrador_OM_situacion_critica.aspx). The International Union for the Conservation of Nature (IUCN) alerted the countries of the Mediterranean basin to the "emergent situation" due to serious mortality events suffered by the fan mussel, putting it in serious risk of extinction. Thus, emergency actions have been implemented by Spanish authorities in which several research institutes from all over the country are involved. The parasite, Haplosporidium pinnae, was recently characterized by histology, TEM, SEM and molecular biology techniques and it was considered responsible for the mass mortality of P. nobilis in the Mediterranean Sea. In this context, the aim of this study has been to develop species-specific quantitative PCR (qPCR) protocol carrying out a fast, specific and effective molecular diagnose of H. pinnae. In this sense, the detection limit for qPCR was equal to 30 copies of SSU rDNA / ng of DNA using plasmid alone and when 100ng DNA of non-infected oyster were added. The qPCR assay revealed that 94% of the 32 analysed mantle tissues of fan mussel were infected by H. pinnae, showing a high sensitivity and specificity for its detection (100% if we don't consider negative and too much degraded samples). This technique will allow us to make quicker follow-ups of the disease, allowing us to get a better understanding of its evolution in order to help in the rescue of P. nobilis populations.

Obesity and its comorbidities are currently considered an epidemic, and the involved pathophysiology is well studied. Hypercaloric diets are tightly related to the obesity etiology and also cause alterations in gut microbiota functionality. Diet and antibiotics are known to play crucial roles in changes in the microbiota ecosystem and the disruption of its balance; therefore, the manipulation of gut microbiota may represent an accurate strategy to understand its relationship with obesity caused by diet. Fecal microbiota transplantation, during which fecal microbiota from a healthy donor is transplanted to an obese subject, has aroused interest as an effective approach for the treatment of obesity. To determine its success, a multiomics approach was used that combined metagenomics and metaproteomics to study microbiota composition and function. To do this, a study was performed in rats that evaluated the effect of a hypercaloric diet on the gut microbiota, and this was combined with antibiotic treatment to deplete the microbiota before fecal microbiota transplantation to verify its effects on gut microbiota-host homeostasis. Our results showed that a high-fat diet induces changes in microbiota biodiversity and alters its function in the host. Moreover, we found that antibiotics depleted the microbiota enough to reduce its bacterial content. Finally, we assessed the use of fecal microbiota transplantation as a complementary obesity therapy, and we found that it reversed the effects of antibiotics and reestablished the microbiota balance, which restored normal functioning and alleviated microbiota disruption. This new approach could be implemented to support the dietary and healthy habits recommended as a first option to maintain the homeostasis of the microbiota.

IntroductionAortic distensibility can be calculated using semi-automated methods to segment the aortic lumen on cine CMR (Cardiovascular Magnetic Resonance) images. However, these methods require visual quality control and manual localization of the region of interest (ROI) of ascending (AA) and proximal descending (PDA) aorta, which limit the analysis in large-scale population-based studies. Using 5100 scans from UK Biobank, this study sought to develop and validate a fully automated method to 1) detect and locate the ROIs of AA and PDA, and 2) provide a quality control mechanism.MethodsThe automated AA and PDA detection-localization algorithm followed these steps: 1) foreground segmentation; 2) detection of candidate ROIs by Circular Hough Transform (CHT); 3) spatial, histogram and shape feature extraction for candidate ROIs; 4) AA and PDA detection using Random Forest (RF); 5) quality control based on RF detection probability. To provide the ground truth, overall image quality (IQ = 0-3 from poor to good) and aortic locations were visually assessed by 13 observers. The automated algorithm was trained on 1200 scans and Dice Similarity Coefficient (DSC) was used to calculate the agreement between ground truth and automatically detected ROIs.ResultsThe automated algorithm was tested on 3900 scans. Detection accuracy was 99.4% for AA and 99.8% for PDA. Aorta localization showed excellent agreement with the ground truth, with DSC ≥ 0.9 in 94.8% of AA (DSC = 0.97 ± 0.04) and 99.5% of PDA cases (DSC = 0.98 ± 0.03). AA×PDA detection probabilities could discriminate scans with IQ ≥ 1 from those severely corrupted by artefacts (AUC = 90.6%). If scans with detection probability < 0.75 were excluded (350 scans), the algorithm was able to correctly detect and localize AA and PDA in all the remaining 3550 scans (100% accuracy).ConclusionThe proposed method for automated AA and PDA localization was extremely accurate and the automatically derived detection probabilities provided a robust mechanism to detect low quality scans for further human review. Applying the proposed localization and quality control techniques promises at least a ten-fold reduction in human involvement without sacrificing any accuracy.

BACKGROUND:Cognitive behavioural therapy (CBT) is aimed to counteract cognitions and behaviours that are considered as dysfunctional. The aim of the study is to test whether the inclusion of a non-counteractive approach (dilemma-focused intervention, DFI) in combination with CBT group therapy will yield better short- and long-term outcomes than an intervention conducted entirely using CBT. METHOD:A total of 128 patients with depression and at least one cognitive conflict, of six health community centres in Barcelona, participated from November of 2011 to December of 2014 in seven weekly group CBT sessions and were then randomly allocated to either DFI or CBT (eight individual sessions each) by an independent researcher. Depressive symptoms were assessed with the Beck Depression Inventory-II at baseline, at the end of therapy and three- and twelve-month follow-ups. Therapists did not participate in any of the assessments nor in the randomisation of patients and evaluators were masked to group assignment. Both intention to treat and complete case analyses were performed using linear mixed models with random effects. FINDINGS:According to intention-to-treat analysis (F2, 179 = 0.69) and complete case analysis (F2, 146 = 0.88), both conditions similarly reduced the severity of symptoms across posttreatment assessments. For the 77 participants (CBTgroup +CBTindividual = 40; CBTgroup+DFIindividual = 37) that completed allocated treatment and one-year follow-up assessment, response and remission rates were relative higher for the DFI condition, however no significant differences were found between treatment conditions. The relapse rates were similar between treatment conditions (CBTgroup +CBTindividual = 7/20; CBTgroup+DFIindividual = 8/22). INTERPRETATION:Although using a counteractive approach across all the treatment sessions is quite effective, it does not seem to be necessary to produce significant improvement. DFI may be considered as an alternative, which could be included in a wider treatment for depression. TRIAL REGISTRATION:ClinicalTrials.gov; ID: NCT01542957.

In combat sports such as taekwondo (TKD), athletes rapidly reduce body weight to achieve a desired weight category. Competition takes place 16-24 h after weigh-in and thus, the recovery time is an important factor for competition performance. The purpose of this study was to investigate the impact of rapid weight reduction (RWR) on athletic performance and associated hemorheological properties considering relevant recovery time. Five male TKD athletes reduced body weight by 5% within 3½ days. A simulated competition day (SCD) was carried out after a 16 h recovery period. Parameters were measured before RWR, at weigh-in and before and after three TKD simulation matches (SMs) at SCD. Same set-up was conducted but without RWR as control. Basal blood parameters, red blood cells (RBC) deformability and aggregation, serum glucose and fibrinogen were determined. During SMs, heart rate (HRpeak, HRmean), oxygen uptake (VO2peak, VO2mean), peak lactate (Peak La-), difference of lactate (ΔLa) and energy systems (anaerobic-alactic, -lactic and aerobic) were analyzed. Basal blood parameters remained unaltered during the interventions. RBC deformability was reduced and aggregation was increased after RWR but values returned to baseline after recovery and were not affected by the SMs. Glucose level was not affected by the interventions. Kick frequency in SMs was higher after RWR which might be responsible for higher HRpeak, VO2peak, VO2mean, Peak La-, ΔLa- and aerobic demand. The 16 h recovery is sufficient to regenerate measured physiological and hemorheological parameters. TKD-specific performance was not negatively affected during SMs after RWR.

In this study, we suggest optimizing the methodology to determine the Cohesion Index (Icd) in order to avoid mistaken characterizations due to powder bulk density. For this purpose, five different excipients, with different bulk densities and of different chemical nature, were compressed at different heights. Their compression and their tablet characterization enable establishing a powder weight for compression in accordance with its bulk density. Therefore, the resulting tablet will have a height within a defined range of heights where it has no critical effects on its hardness. Then, the impact of this optimization is shown in a formula development, one of the main SeDeM's applications. A mathematical equation was used to calculate the theoretical amount of excipient to formulate the API according to both methodologies. The compression results demonstrate that the characterization with the NM-Icd is more accurate than the previous one while preserving its simplicity.

Only a small fraction of HIV-1-infected patients develop broadly neutralizing antibodies (bNAbs), a process generally associated to chronic antigen stimulation. It has been described that rare aviremic HIV-1-infected patients can generate bNAbs but this issue remains controversial. To address this matter we have assessed bNAb responses in a large cohort of long-term non-progressors (LTNPs) with low or undetectable viremia.Samples from the LTNP cohort of the Spanish AIDS Research Network (87 elite and 42 viremic controllers) and a control population of 176 viremic typical-progressors (TPs) were screened for bNAbs using Env-recombinant viruses. bNAb specificities were studied by ELISA using mutated gp120, neutralization assays with mutated viruses, and peptide competition. Epitope specificities were also elucidated from the serum pattern of neutralization against a panel of diverse HIV-1 isolates.Broadly neutralizing sera were found among 9.3% LTNPs, both elite (7%) and viremic controllers (14%). Within the broadly neutralizing sera, CD4 binding site antibodies were detected by ELISA in 4/12 LTNPs (33%), and 16/33 of TPs (48%). Anti-MPER antibodies were detected in 6/12 LTNPs (50%) and 14/33 TPs (42%) whereas glycan-dependent HIV-1 bNAbs were more frequent in LTNPs (11/12, 92%) as compared to TPs (12/33, 36%). A good concordance between standard serum mapping and neutralization-based mapping was observed.LTNPs, both viremic and elite controllers, showed broad humoral immune responses against HIV-1, including activity against many major epitopes involved in bNAbs-mediated protection.

The presence of standardised tools and methods to measure and represent accurately biological parts and functions is a prerequisite for successful metabolic engineering and crucial to understand and predict the behaviour of synthetic genetic circuits. Many synthetic gene networks are based on transcriptional circuits, thus information on transcriptional and translational activity is important for understanding and fine-tuning the synthetic function. To this end, we have developed a toolkit to analyse systematically the transcriptional and translational activity of a specific synthetic part in vivo. It is based on the plasmid pTRA and allows the assignment of specific transcriptional and translational outputs to the gene(s) of interest (GOI) and to compare different genetic setups. By this, the optimal combination of transcriptional strength and translational activity can be identified. The design is tested in a case study using the gene encoding the fluorescent mCherry protein as GOI. We show the intracellular dynamics of mRNA and protein formation and discuss the potential and shortcomings of the pTRA plasmid.

Assessment of coronary stenosis severity is crucial in clinical practice. This study proposes a novel method to generate 3D models of stenotic coronary arteries, directly from 2D coronary images, and suitable for immediate assessment of the stenosis severity.From multiple 2D X-ray coronary arteriogram projections, 2D vessels were extracted. A 3D centreline was reconstructed as intersection of surfaces from corresponding branches. Next, 3D luminal contours were generated in a two-step process: first, a Non-Uniform Rational B-Spline (NURBS) circular contour was designed and, second, its control points were adjusted to interpolate computed 3D boundary points. Finally, a 3D surface was generated as an interpolation across the control points of the contours and used in the analysis of the severity of a lesion. To evaluate the method, we compared 3D reconstructed lesions with Optical Coherence Tomography (OCT), an invasive imaging modality that enables high-resolution endoluminal visualization of lesion anatomy.Validation was performed on routine clinical data. Analysis of paired cross-sectional area discrepancies indicated that the proposed method more closely represented OCT contours than conventional approaches in luminal surface reconstruction, with overall root-mean-square errors ranging from 0.213mm2 to 1.013mm2, and maximum error of 1.837mm2. Comparison of volume reduction due to a lesion with corresponding FFR measurement suggests that the method may help in estimating the physiological significance of a lesion.The algorithm accurately reconstructed 3D models of lesioned arteries and enabled quantitative assessment of stenoses. The proposed method has the potential to allow immediate analysis of the stenoses in clinical practice, thereby providing incremental diagnostic and prognostic information to guide treatments in real time and without the need for invasive techniques.

Several RT-PCR and genome sequencing strategies exist for the resolution of Foot-and-Mouth Disease virus (FMDV). While these approaches are relatively straightforward, they can be vulnerable to failure due to the unpredictable nature of FMDV genome sequence variations. Sequence independent single primer amplification (SISPA) followed by genotyping microarray offers an attractive unbiased approach to FMDV characterization. Here we describe a custom FMDV microarray and a companion feature and template-assisted assembler software (FAT-assembler) capable of resolving virus genome sequence using a moderate number of conserved microarray features. The results demonstrate that this approach may be used to rapidly characterize naturally occurring FMDV as well as an engineered chimeric strain of FMDV. The FAT-assembler, while applied to resolving FMDV genomes, represents a new bioinformatics approach that should be broadly applicable to interpreting microarray genotyping data for other viruses or target organisms.

To investigate the role of the protein C system, endothelial protein C receptor (EPCR) and thrombomodulin (TM) in the pathogenesis of malaria-associated acute respiratory distress syndrome (ARDS) in relation to hemozoin and proinflammatory cytokines-induced type II pneumocyte injury and -aggravated pulmonary resolution. A total of 29 left-over lung specimens that were obtained from patients who died from severe falciparum malaria were examined. Histopathological, immunohistochemical and electron microscopic analyses revealed that ARDS coexisted with pulmonary edema and systemic bleeding; the severity was dependent on the level of hemozoin deposition in the lung and internal alveolar hemorrhaging. The loss of EPCR and TM was primarily identified in ARDS patients and was related to the level of hemozoin, parasitized red blood cell (PRBC) and white blood cell accumulation in the lung. Moreover, an in vitro analysis demonstrated that interleukin-13 and -31 and hemozoin induced pneumocytic cell injury and apoptosis, as assessed by EB/AO staining, electron microscopy and the up-regulation of CARD-9 mRNA (caspase recruitment domain-9 messenger-ribonucleic acid). The dysregulation of EPCR and TM in the lung, especially in those with increased levels of hemozoin, may play an important role in the pathogenesis of malaria-associated ARDS through an apoptotic pathway.

The underlying pathology of arsenic-related cardiovascular disease (CVD) is unknown. Few studies have evaluated pathways through thrombosis and inflammation for arsenic-related CVD, especially at low-moderate arsenic exposure levels (

The aim of this systematic review and meta-analysis is to synthesize the available evidence in scientific papers of smokefree legislation effects on respiratory diseases and sensory and respiratory symptoms (cough, phlegm, red eyes, runny nose) among all populations.Systematic review and meta-analysis were carried out. A search between January 1995 and February 2015 was performed in PubMed, EMBASE, Cochrane Library, Scopus, Web of Science, and Google Scholar databases. Inclusion criteria were: 1) original scientific studies about smokefree legislation, 2) Data before and after legislation were collected, and 3) Impact on respiratory and sensory outcomes were assessed. Paired reviewers independently carried out the screening of titles and abstracts, data extraction from full-text articles, and methodological quality assessment.A total number of 1606 papers were identified. 50 papers were selected, 26 were related to symptoms (23 concerned workers). Most outcomes presented significant decreases in the percentage of people suffering from them, especially in locations with comprehensive measures and during the immediate post-ban period (within the first six months). Four (50%) of the papers concerning pulmonary function reported some significant improvement in expiratory parameters. Significant decreases were described in 13 of the 17 papers evaluating asthma hospital admissions, and there were fewer significant reductions in chronic obstructive pulmonary disease admissions (range 1-36%) than for asthma (5-31%). Six studies regarding different respiratory diseases showed discrepant results, and four papers about mortality reported significant declines in subgroups. Low bias risk was present in 23 (46%) of the studies.Smokefree legislation appears to improve respiratory and sensory symptoms at short term in workers (the overall effect being greater in comprehensive smokefree legislation in sensory symptoms) and, to a lesser degree, rates of hospitalization for asthma.

Halophilic bacteria use a variety of osmoregulatory methods, such as the accumulation of one or more compatible solutes. The wide diversity of compounds that can act as compatible solute complicates the task of understanding the different strategies that halophilic bacteria use to cope with salt. This is specially challenging when attempting to go beyond the pathway that produces a certain compatible solute towards an understanding of how the metabolic network as a whole addresses the problem. Metabolic reconstruction based on genomic data together with Flux Balance Analysis (FBA) is a promising tool to gain insight into this problem. However, as more of these reconstructions become available, it becomes clear that processes predicted by genome annotation may not reflect the processes that are active in vivo. As a case in point, E. coli is unable to grow aerobically on citrate in spite of having all the necessary genes to do it. It has also been shown that the realization of this genetic potential into an actual capability to metabolize citrate is an extremely unlikely event under normal evolutionary conditions. Moreover, many marine bacteria seem to have the same pathways to metabolize glucose but each species uses a different one. In this work, a metabolic network inferred from genomic annotation of the halophilic bacterium Halomonas elongata and proteomic profiling experiments are used as a starting point to motivate targeted experiments in order to find out some of the defining features of the osmoregulatory strategies of this bacterium. This new information is then used to refine the network in order to describe the actual capabilities of H. elongata, rather than its genetic potential.

The aim of this study was to examine the association of sedentary behaviour patterns with frailty in older people.Clinical setting.Cross-sectional, observational study.A triaxial accelerometer was used in a subsample from the Toledo Study for Healthy Aging (519 participants, 67-97 years) to assess several sedentary behaviour patterns including sedentary time per day, the number and duration (min) of breaks in sedentary time per day, and the proportion of the day spent in sedentary bouts of 10 minutes or more. Frailty was assessed using the Frailty Trait Scale (FTS). Regression analysis was used to ascertain the associations between sedentary behaviour patterns and frailty.Sedentary time per day and the proportion of the day spent in sedentary bouts of 10 minutes or more, were positively associated with frailty in the study sample. Conversely, the time spent in breaks in sedentary time was negatively associated with frailty.In summary, breaking up sedentary time and time spent in sedentary behaviour are associated with frailty in older people.

[This corrects the article DOI: 10.1371/journal.pone.0173580.].

By searching a clinical database of over 60,000 individuals referred for array-based CNV analyses and online resources, we identified four males from three families with intellectual disability, developmental delay, hypotonia, joint hypermobility and relative macrocephaly who carried small, overlapping deletions of Xp11.22. The maximum region of overlap between their deletions spanned ~430 kb and included two pseudogenes, CENPVL1 and CENPVL2, whose functions are not known, and two protein coding genes-the G1 to S phase transition 2 gene (GSPT2) and the MAGE family member D1 gene (MAGED1). Deletions of this ~430 kb region have not been previously implicated in human disease. Duplications of GSPT2 have been documented in individuals with intellectual disability, but the phenotypic consequences of a loss of GSPT2 function have not been elucidated in humans or mouse models. Changes in MAGED1 have not been associated with intellectual disability in humans, but loss of MAGED1 function is associated with neurocognitive and neurobehavioral phenotypes in mice. In all cases, the Xp11.22 deletion was inherited from an unaffected mother. Studies performed on DNA from one of these mothers did not show evidence of skewed X-inactivation. These results suggest that deletions of an ~430 kb region on chromosome Xp11.22 that encompass CENPVL1, CENPVL2, GSPT2 and MAGED1 cause a distinct X-linked syndrome characterized by intellectual disability, developmental delay, hypotonia, joint hypermobility and relative macrocephaly. Loss of GSPT2 and/or MAGED1 function may contribute to the intellectual disability and developmental delay seen in males with these deletions.

Plant-pathogenic Xanthomonas bacteria inject transcription activator-like effector proteins (TALEs) into host cells to specifically induce transcription of plant genes and enhance susceptibility. Although the DNA-binding mode is well-understood it is still ambiguous how TALEs initiate transcription and whether additional promoter elements are needed to support this. To systematically dissect prerequisites for transcriptional initiation the activity of one TALE was compared on different synthetic Bs4 promoter fragments. In addition, a large collection of artificial TALEs spanning the OsSWEET14 promoter was compared. We show that the presence of a TALE alone is not sufficient to initiate transcription suggesting the requirement of additional supporting promoter elements. At the OsSWEET14 promoter TALEs can initiate transcription from various positions, in a synergistic manner of multiple TALEs binding in parallel to the promoter, and even by binding in reverse orientation. TALEs are known to shift the transcriptional start site, but our data show that this shift depends on the individual position of a TALE within a promoter context. Our results implicate that TALEs function like classical enhancer-binding proteins and initiate transcription in both orientations which has consequences for in planta target gene prediction and design of artificial activators.

As they undergo phagocytosis, most early apoptotic cells negatively regulate proinflammatory signaling and were suggested as a major mechanism in the resolution of inflammation. The dextran sulfate sodium model is generally viewed as an epithelial damage model suited to investigate innate immune responses. Macrophages primed with LPS and subsequently exposed to DSS secrete high levels of IL-1β in an NLRP3-, ASC-, and caspase-1-dependent manner. The aim of this research was to test the therapeutic effect of a single dose of apoptotic cells in a DSS-colitis model and to explore possible mechanisms. Primary peritoneal macrophages, the DSS mice model, and Nlrp3-deficient mice, were used to assess the effect apoptotic cells on colitis. Immunohistochemistry, flow-cytometer, and western blots helped to explore the effect and mechanisms. Using a variety of NLRP3 triggering mechanisms, we show that apoptotic cells negatively regulate NF-κB and NLRP3 activation in primary peritoneal macrophages, at pre- and post-transcription levels, via inhibition of reactive oxygen species, lysosomal stabilization, and blocking K+ efflux. This property of apoptotic cells is demonstrated in a dramatic clinical, histological, and immunological amelioration of DSS colitis in Balb/c and B6 mice following a single administration of apoptotic cells.