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Plain Language Summaries (PLS) offer a promising solution to make meta-analytic psychological research more accessible for non-experts and laypeople. However, existing writing guidelines for this type of publication are seldom grounded in empirical studies. To address this and to test two versions of a new PLS guideline, we investigated the impact of PLSs of psychological meta-analyses on laypeoples' PLS-related knowledge and their user experience (accessibility, understanding, empowerment). In a preregistered online-study, N = 2,041 German-speaking participants read two PLSs. We varied the inclusion of a disclaimer on PLS authorship, a statement on the causality of effects, additional information on community augmented meta-analyses (CAMA) and the PLS guideline version. Results partially confirmed our preregistered hypotheses: Participants answered knowledge items on CAMA more correctly when a PLS contained additional information on CAMA, and there were no user experience differences between the old and the new guideline versions. Unexpectedly, a priori hypotheses regarding improved knowledge via the use of a disclaimer and a causality statement were not confirmed. Reasons for this, as well as general aspects related to science communication via PLSs aimed at educating laypeople, are discussed.

Whenever we are confronted with action opportunities in everyday life, e.g., when passing an opening, we rely on our ability to precisely estimate our own bodily capabilities in relation to the environmental conditions. So-called affordance judgments can be affected after brain damage. Previous studies with healthy adults showed that such judgments appeared to be trainable within one session. In the current study, we examined whether stroke patients with either right brain damage (n = 30) or left brain damage (n = 30) may similarly profit from training in an aperture task. Further, the role of neuropsychological deficits in trainability was investigated. In the administered task, stroke patients decided whether their hand would fit into a presented opening with varying horizontal width (Aperture Task). During one training session, patients were asked to try to fit their hand into the opening and received feedback on their decisions. We analyzed accuracy and the detection theory parameters perceptual sensitivity and judgment tendency. Both patients with right brain damage and patients with left brain damage showed improved performance during training as well as post training. High variability with differential profiles of trainability was revealed in these patients. Patients with impaired performance in a visuo-spatial or motor-cognitive task appeared to profit considerably from the target-driven action phase with feedback, but the performance increase in judgments did not last when the action was withdrawn. Future studies applying lesion analysis with a larger sample may shed further light on the dissociation in the trainability of affordance judgments observed in patients with versus without visuo-spatial or motor-cognitive deficits.

Neonatal sepsis is a serious public health problem; however, there is substantial heterogeneity in the outcomes measured and reported in research evaluating the effectiveness of the treatments. Therefore, we aim to develop a Core Outcome Set (COS) for studies evaluating the effectiveness of treatments for neonatal sepsis. Since a systematic review of key outcomes from randomised trials of therapeutic interventions in neonatal sepsis was published recently, we will complement this with a qualitative systematic review of the key outcomes of neonatal sepsis identified by parents, other family members, parent representatives, healthcare providers, policymakers, and researchers. We will interpret the outcomes of both studies using a previously established framework. Stakeholders across three different groups i.e., (1) researchers, (2) healthcare providers, and (3) patients' parents/family members and parent representatives will rate the importance of the outcomes in an online Real-Time Delphi Survey. Afterwards, consensus meetings will be held to agree on the final COS through online discussions with key stakeholders. This COS is expected to minimize outcome heterogeneity in measurements and publications, improve comparability and synthesis, and decrease research waste.

Hemostasis is the cessation of bleeding due to the formation of a blood clot. After the completion of wound healing, the blood clot is typically dissolved through the natural process of fibrinolysis, the enzymatic digestion by plasmin of the fibrin fibers that make up its structural scaffold. In vitro studies of fibrinolysis reveal mechanisms regulating these processes and often employ fluorescent microscopy to observe protein colocalization and fibrin digestion. In this study, we investigate the effects of labeling a fibrin network with 20 nm diameter fluorescent beads (fluorospheres) for the purpose of studying fibrinolysis. We observed fibers and 2-D fibrin networks labeled with fluorospheres during fibrinolysis. We found that the labeling of fibrin with fluorospheres can alter fibrinolytic mechanisms. In previous work, we showed that, during lysis, fibrin fibers are cleaved into two segments at a single location. Herein we demonstrate that fibrinolysis can be altered by the concentration of fluorospheres used to label the fibers, with high concentrations of fluorospheres leading to very minimal cleaving. Furthermore, fibers that are left uncleaved after the addition of plasmin often elongate, losing their inherent tension throughout the imaging process. Elongation was especially prominent among fibers that had bundled together due to other cleavage events and was dependent on the concentration of fluorophores used to label fibers. Of the fibers that do cleave, the site at which they cleave also shows a predictable trend dependent on fluorosphere concentration; low concentrations heavily favor cleavage locations at either end of fibrin fiber and high concentrations show no disparity between the fiber ends and other locations along the fiber. After the initial cleavage event bead concentration also affects further digestion, as higher bead concentrations exhibited a larger population of fibers that did not digest further. The results described in this paper indicate that fluorescent labeling strategies can impact fibrinolysis results.

Plain language summaries (PLSs) have been introduced to communicate research in an understandable way to a nonexpert audience. Guidelines for writing PLSs have been developed and empirical research on PLSs has been conducted, but terminology and research approaches in this comparatively young field vary considerably. This prompted us to review the current state of the art of the theoretical and empirical literature on PLSs. The two main objectives of this review were to develop a conceptual framework for PLS theory, and to synthesize empirical evidence on PLS criteria. We began by searching Web of Science, PubMed, PsycInfo and PSYNDEX (last search 07/2021). In our review, we included empirical investigations of PLSs, reports on PLS development, PLS guidelines, and theoretical articles referring to PLSs. A conceptual framework was developed through content analysis. Empirical studies investigating effects of PLS criteria on defined outcomes were narratively synthesized. We identified 7,714 records, of which 90 articles met the inclusion criteria. All articles were used to develop a conceptual framework for PLSs which comprises 12 categories: six of PLS aims and six of PLS characteristics. Thirty-three articles empirically investigated effects of PLSs on several outcomes, but study designs were too heterogeneous to identify definite criteria for high-quality PLSs. Few studies identified effects of various criteria on accessibility, understanding, knowledge, communication of research, and empowerment. We did not find empirical evidence to support most of the criteria we identified in the PLS writing guidelines. We conclude that although considerable work on establishing and investigating PLSs is available, empirical evidence on criteria for high-quality PLSs remains scarce. The conceptual framework developed in this review may provide a valuable starting point for future guideline developers and PLS researchers.

Cistanthe longiscapa is an endemic annual herb and characteristic element of the Chilean Atacama Desert. Principal threats are the destruction of its seed deposits by human activities and reduced germination rates due to the decreasing occurrence of precipitation events. To enable population genetic and phylogeographic analyses in this species we performed paired-end shotgun sequencing (2x100 bp) of genomic DNA on the Illumina HiSeq platform and identified microsatellite (SSR) loci in the resulting sequences. From 29 million quality-filtered read pairs we obtained 549,174 contigs (average length 614 bp; N50 = 904). Searching for SSRs revealed 10,336 loci with microsatellite motifs. Initially, we designed primers for 96 loci, which were tested for PCR amplification on three C. longiscapa individuals. Successfully amplifying loci were further tested on eight individuals to screen for length variation in the resulting amplicons, and the alleles were exemplarily sequenced to infer the basis for the observed length variation. Finally we arrived at 26 validated SSR loci for population studies in C. longiscapa, which resulted in 146 bi-allelic SSR markers in our test sample of eight individuals. The genomic sequences were also used to assemble the plastid genome of C. longiscapa, which provides an additional set of maternally inherited genetic markers.

Crohn disease (CD), a sub-entity of inflammatory bowel disease (IBD), is a complex polygenic disorder. Although recent studies have successfully identified CD-associated genetic variants, these susceptibility loci explain only a fraction of the heritability of the disease. Here, we report on a multi-stage genome-wide scan of 393 German CD cases and 399 controls. Among the 116,161 single-nucleotide polymorphisms tested, an association with the known CD susceptibility gene NOD2, the 5q31 haplotype, and the recently reported CD locus at 5p13.1 was confirmed. In addition, SNP rs1793004 in the gene encoding nel-like 1 precursor (NELL1, chromosome 11p15.1) showed a consistent disease-association in independent German population- and family-based samples (942 cases, 1082 controls, 375 trios). Subsequent fine mapping and replication in an independent sample of 454 French/Canadian CD trios supported the authenticity of the NELL1 association. Further confirmation in a large German ulcerative colitis (UC) sample indicated that NELL1 is a ubiquitous IBD susceptibility locus (combined p

BackgroundAcute disease outbreaks such as the COVID-19 pandemic cause a high burden of psychological distress in people worldwide. Interventions to enable people to better cope with such distress should be based on the best available evidence. We therefore performed a scoping review to systematically identify and summarize the available literature of interventions that target the distress of people in the face of highly contagious disease outbreaks.MethodsMEDLINE, Cochrane CENTRAL, Web of Science (January 2000 to May 7, 2020), and reference lists were systematically searched and screened by two independent reviewers. Quantitative and qualitative studies investigating the effects of psychological interventions before, during, and after outbreaks of highly contagious emerging infectious diseases, such as SARS, MERS, Ebola, or COVID-19 were included. Study effects were grouped (e.g. for healthcare professionals, community members, people at risk) and intervention contents at the individual and organizational level summarized. We assessed the level of evidence using a modified scheme from the Oxford Centre for Evidence-based Medicine and the Australian National Health and Medical Research Council.ResultsOf 4030 records found, 19 studies were included (two RCTs). Most interventions were delivered during-exposure and face-to-face, focused on healthcare workers and crisis personnel, and combined psychoeducation with training of coping strategies. Based on two high-quality studies, beneficial effects were reported for resilience factors (e.g. positive cognitive appraisal) and professional attitudes of healthcare workers, with mixed findings for mental health (e.g. depression). Across all studies, there was positive qualitative feedback from participants and facilitators. We identified seven ongoing studies mostly using online- and mobile-based deliveries.ConclusionsThere is preliminary evidence for beneficial effects of interventions to enable people to better cope with the distress of highly contagious emerging disease outbreaks. Besides the need for more high-quality studies, the summarized evidence may inform decision makers to plan interventions during the current pandemic and to develop pandemic preparedness plans.

BackgroundHospital readmissions place a major burden on patients and health care systems worldwide, but little is known about patterns and timing of readmissions in Germany.MethodsWe used German health insurance claims (AOK, 2011-2016) of patients ≥ 65 years hospitalized for acute myocardial infarction (AMI), heart failure (HF), a composite of stroke, transient ischemic attack, or atrial fibrillation (S/AF), chronic obstructive pulmonary disease (COPD), type 2 diabetes mellitus, or osteoporosis to identify hospital readmissions within 30 or 90 days. Readmissions were classified into all-cause, specific, and non-specific and their characteristics were analyzed.ResultsWithin 30 and 90 days, about 14-22% and 27-41% index admissions were readmitted for any reason, respectively. HF and S/AF contributed most index cases, and HF and COPD accounted for most all-cause readmissions. Distributions and ratios of specific to non-specific readmissions were disease-specific with highest specific readmissions rates among COPD and AMI.ConclusionGerman claims are well-suited to investigate readmission causes if longer periods than 30 days are evaluated. Conditions closely related with the primary disease are the most frequent readmission causes, but multiple comorbidities among readmitted cases suggest that a multidisciplinary care approach should be implemented vigorously addressing comorbidities already during the index hospitalization.

BackgroundThe 2016 WHO Standards for improving quality of maternal and newborn care in health facilities established patient experience of care as a core indicator of quality. Global health experts have described loss of autonomy and disrespect as mistreatment. Risk of disrespect and abuse is higher when patient and care provider opinions differ, but little is known about service users experiences when declining aspects of their maternity care.MethodsTo address this gap, we present a qualitative content analysis of 1540 written accounts from 892 service users declining or refusing care options throughout childbearing with a large, geographically representative sample (2900) of childbearing women in British Columbia who participated in an online survey with open-ended questions eliciting care experiences.FindingsFour themes are presented: 1) Contentious interactions: "I fought my entire way", describing interactions as fraught with tension and recounting stories of "fighting" for the right to refuse a procedure/intervention; 2) Knowledge as control or as power: "like I was a dim girl", both for providers as keepers of medical knowledge and for clients when they felt knowledgeable about procedures/interventions; 3) Morbid threats: "do you want your baby to die?", coercion or extreme pressure from providers when clients declined interventions; 4) Compliance as valued: "to be a 'good client'", recounting compliance or obedience to medical staff recommendations as valuable social capital but suppressing desire to ask questions or decline care.ConclusionWe conclude that in situations where a pregnant person declines recommended treatment, or requests treatment that a care provider does not support, tension and strife may ensue. These situations deprioritize and decenter a woman's autonomy and preferences, leading care providers and the culture of care away from the principles of respect and person-centred care.

[This corrects the article DOI: 10.1371/journal.pone.0068033.].

BACKGROUND:Multiple myeloma (MM) is a hematological malignancy characterized by the clonal expansion of malignant plasma cells. Though durable remissions are possible, MM is considered incurable, with relapse occurring in almost all patients. There has been limited data reported on the lipid metabolism changes in plasma cells during MM progression. Here, we evaluated the feasibility of concurrent lipidomics and proteomics analyses from patient plasma cells, and report these data on a limited number of patient samples, demonstrating the feasibility of the method, and establishing hypotheses to be evaluated in the future. METHODS:Plasma cells were purified from fresh bone marrow aspirates using CD138 microbeads. Proteins and lipids were extracted using a bi-phasic solvent system with methanol, methyl tert-butyl ether, and water. Untargeted proteomics, untargeted and targeted lipidomics were performed on 7 patient samples using liquid chromatography-mass spectrometry. Two comparisons were conducted: high versus low risk; relapse versus newly diagnosed. Proteins and pathways enriched in the relapsed group was compared to a public transcriptomic dataset from Multiple Myeloma Research Consortium reference collection (n = 222) at gene and pathways level. RESULTS:From one million purified plasma cells, we were able to extract material and complete untargeted (~6000 and ~3600 features in positive and negative mode respectively) and targeted lipidomics (313 lipids), as well as untargeted proteomics analysis (~4100 reviewed proteins). Comparative analyses revealed limited differences between high and low risk groups (according to the standard clinical criteria), hence we focused on drawing comparisons between the relapsed and newly diagnosed patients. Untargeted and targeted lipidomics indicated significant down-regulation of phosphatidylcholines (PCs) in relapsed MM. Although there was limited overlap of the differential proteins/transcripts, 76 significantly enriched pathways in relapsed MM were common between proteomics and transcriptomics data. Further evaluation of transcriptomics data for lipid metabolism network revealed enriched correlation of PC, ceramide, cardiolipin, arachidonic acid and cholesterol metabolism pathways to be exclusively correlated among relapsed but not in newly-diagnosed patients. CONCLUSIONS:This study establishes the feasibility and workflow to conduct integrated lipidomics and proteomics analyses on patient-derived plasma cells. Potential lipid metabolism changes associated with MM relapse warrant further investigation.

Extreme arid conditions in the Atacama Desert in northern Chile have created a unique vegetation almost entirely restricted to the desert margins along the coast of the Pacific Ocean and the Andean range. In this study we provide data on the desert vegetation along elevational gradients at four localities from the western Andean slopes, between 19° and 21° S. Additionally, zonation of floristic data was explored. Three altitudinal zones could be classified and described in detail for each locality. Conspicuously divergent floras in the Atacama Desert have been recorded in the coastal 'lomas formations' and in the Andean desert vegetation, separated by a narrow band of absolute desert. In this study, we investigate the floristic relationships between both regions by implementing similarity analyses for 21 localities from the coastal and Andean deserts in northern Chile. Our results show a drastic east-west divergence in pairwise floristic similarity, which is in stark contrast to a weaker north-south divergence. A biotic barrier, preventing plant exchange from east to west and vice versa, imposed by the hyperarid conditions of the absolute desert, is one possible explanation for this finding. Moreover, the coastal and Andean deserts likely represent ecologically divergent habitats, e.g., in rainfall seasonality. Essential differences in factors determining plant life between both regions have probably contributed to a divergent evolution of the floras. Both explanations-ecological divergence and ecogeographical isolation-are not mutually exclusive, but likely complementary. We also combined floristic data from northern Chile and southern Peru. Similarity analyses of this combined dataset provide first floristic evidence for the existence of a biotic north-south corridor along the western slope of the Andes. Sub-Andean distributions of several species are discussed in the light of floristic connectivity between the Peruvian and Chilean Andean floristic clusters.

We investigated rock varnish, a thin, manganese- and iron-rich, dark surface crust, on basaltic lava flows and petroglyphs in the Owens and Rose Valleys (California) by portable X-ray fluorescence (pXRF) and femtosecond laser-ablation inductively-coupled-plasma mass spectrometry (fs-LA-ICPMS). The major element composition of the varnish was consistent with a mixture of Mn-Fe oxyhydroxides and clay minerals. As expected, it contained elevated concentrations of elements that are typically enriched in rock varnish, e.g., Mn, Pb, Ba, Ce, and Co, but also showed unusually high enrichments in U, Cu, and Th. The rare earth and yttrium (REY) enrichment pattern revealed a very strong positive cerium (Ce) anomaly and distinct negative europium (Eu) and Y anomalies. The light rare earth elements (REE) were much more strongly enriched than the heavy REY. These enrichment patterns are consistent with a formation mechanism by leaching of Mn and trace elements from aeolian dust, reprecipitation of Mn and Fe as oxyhydroxides, and scavenging of trace elements by these oxyhydroxides. We inferred accumulation rates of Mn and Fe in the varnish from their areal densities measured by pXRF and the known ages of some of the lava flow surfaces. The areal densities of Mn and Fe, as well as their accumulation rates, were comparable to our previous results from the desert of Saudi Arabia. There was a moderate dependence of the Mn areal density on the inclination of the rock surfaces, but no relationship to its cardinal orientation. We attempted to use the degree of varnish regrowth on the rock art surfaces as an estimate of their age. While an absolute dating of the petroglyphs was not possible because of the lack of suitable calibration surfaces and a considerable amount of variability, the measured degree of varnish regrowth on the various petroglyphs was consistent with chronologies based on archeological and other archaeometric techniques. In particular, our results suggest that rock art creation in the study area continued over an extended period of time, possibly starting around the Pleistocene/Holocene transition and extending into the last few centuries.

We recently reported a family-based genome wide association study (GWAS) for pediatric stroke pointing our attention to two significantly associated genes of the ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) gene family ADAMTS2 (rs469568, p = 8x10-6) and ADAMTS12 (rs1364044, p = 2.9x10-6). To further investigate these candidate genes, we applied a targeted resequencing approach on 48 discordant sib-pairs for pediatric stroke followed by genotyping of the detected non-synonymous variants in the full cohort of 270 offspring trios and subsequent fine mapping analysis. We identified eight non-synonymous SNPs in ADAMTS2 and six in ADAMTS12 potentially influencing the respective protein function. These variants were genotyped within a cohort of 270 affected offspring trios, association analysis revealed the ADAMTS12 variant rs77581578 to be significantly under-transmitted (p = 6.26x10-3) to pediatric stroke patients. The finding was validated in a pediatric venous thromboembolism (VTE) cohort of 189 affected trios. Subsequent haplotype analysis of ADAMTS12 detected a significantly associated haplotype comprising the originally identified GWAS variant. Several ADAMTS genes such as ADAMTS13 are involved in thromboembolic disease process. Here, we provide further evidence for ADAMTS12 to likely play a role in pediatric stroke. Further functional studies are warranted to assess the functional role of ADAMTS12 in the pathogenesis of stroke.

Breast cancer is the second leading cause of cancer-related mortality in women. Various nutritional compounds possess anti-carcinogenic properties which may be mediated through their effects on the gut microbiota and its production of short-chain fatty acids (SCFAs) for the prevention of breast cancer. We evaluated the impact of broccoli sprouts (BSp), green tea polyphenols (GTPs) and their combination on the gut microbiota and SCFAs metabolism from the microbiota in Her2/neu transgenic mice that spontaneously develop estrogen receptor-negative [ER(-)] mammary tumors. The mice were grouped based on the dietary treatment: control, BSp, GTPs or their combination from beginning in early life (BE) or life-long from conception (LC). We found that the combination group showed the strongest inhibiting effect on tumor growth volume and a significant increase in tumor latency. BSp treatment was integrally more efficacious than the GTPs group when compared to the control group. There was similar clustering of microbiota of BSp-fed mice with combination-fed mice, and GTPs-fed mice with control-fed mice at pre-tumor in the BE group and at pre-tumor and post-tumor in the LC group. The mice on all dietary treatment groups incurred a significant increase of Adlercreutzia, Lactobacillus genus and Lachnospiraceae, S24-7 family in the both BE and LC groups. We found no change in SCFAs levels in the plasma of BSp-fed, GTPs-fed and combination-fed mice of the BE group. Marked changes were observed in the mice of the LC group consisting of significant increases in propionate and isobutyrate in GTPs-fed and combination-fed mice. These studies indicate that nutrients such as BSp and GTPs differentially affect the gut microbial composition in both the BE and LC groups and the key metabolites (SCFAs) levels in the LC group. The findings also suggest that temporal factors related to different time windows of consumption during the life-span can have a promising influence on the gut microbial composition, SCFAs profiles and ER(-) breast cancer prevention.

Cholangiocarcinoma (CCA) is a primary malignant tumor of the epithelial lining of biliary track associated with endemic Opisthorchis viverrini (Ov) infection in northeastern Thailand. Ov-associated periductal fibrosis (PDF) is the precancerous lesion for CCA, and can be detected by ultrasonography (US) to facilitate early detection. However, US cannot be used to distinguish PDF from cancer. Therefore, the objective of this study was to discover and qualify potential urine biomarkers for CCA detection in at-risk population. Biomarker discovery was conducted on pooled urine samples, 42 patients per group, with PDF or normal bile duct confirmed by ultrasound. After depletion of high abundance proteins, 338 urinary proteins were identified from the 3 samples (normal-US, PDF-US, CCA). Based on fold change and literature review, 70 candidate proteins were selected for qualification by multiple reaction monitoring mass spectrometry (MRM-MS) in 90 individual urine samples, 30 per group. An orthogonal signal correction projection to latent structures discriminant analysis (O-PLS-DA) multivariate model constructed from the 70 candidate biomarkers significantly discriminated CCA from normal and PDF groups (P = 0.003). As an independent validation, the expression of 3 candidate proteins was confirmed by immunohistochemistry in CCA tissues: Lysosome associated membrane glycoprotein 1 (LAMP1), lysosome associated membrane glycoprotein 2 (LAMP2) and cadherin-related family member 2 (CDHR2). Further evaluation of these candidate biomarkers in a larger cohort is needed to support their applicability in a clinical setting for screening and monitoring early CCA and for CCA surveillance.

IntroductionInjury prevention programs (IPPs) are an inherent part of training in recreational and professional sports. Providing performance-enhancing benefits in addition to injury prevention may help adjust coaches and athletes' attitudes towards implementation of injury prevention into daily routine. Conventional thinking by players and coaches alike seems to suggest that IPPs need to be specific to one's sport to allow for performance enhancement. The systematic literature review aims to firstly determine the IPPs nature of exercises and whether they are specific to the sport or based on general conditioning. Secondly, can they demonstrate whether general, sports-specific or even mixed IPPs improve key performance indicators with the aim to better facilitate long-term implementation of these programs?MethodsPubMed and Web of Science were electronically searched throughout March 2018. The inclusion criteria were randomized control trials, publication dates between Jan 2006 and Feb 2018, athletes (11-45 years), injury prevention programs and included predefined performance measures that could be categorized into balance, power, strength, speed/agility and endurance. The methodological quality of included articles was assessed with the Cochrane Collaboration assessment tools.ResultsOf 6619 initial findings, 22 studies met the inclusion criteria. In addition, reference lists unearthed a further 6 studies, making a total of 28. Nine studies used sports specific IPPs, eleven general and eight mixed prevention strategies. Overall, general programs ranged from 29-57% in their effectiveness across performance outcomes. Mixed IPPs improved in 80% balance outcomes but only 20-44% in others. Sports-specific programs led to larger scale improvements in balance (66%), power (83%), strength (75%), and speed/agility (62%).ConclusionSports-specific IPPs have the strongest influence on most performance indices based on the significant improvement versus control groups. Other factors such as intensity, technical execution and compliance should be accounted for in future investigations in addition to exercise modality.

METHODS:Our multidisciplinary team examined published regulatory data to inform a 50-state database describing the environment for midwifery practice and interprofessional collaboration. Items (110) detailed differences across jurisdictions in scope of practice, autonomy, governance, and prescriptive authority; as well as restrictions that can affect patient safety, quality, and access to maternity providers across birth settings. A nationwide survey of state regulatory experts (n = 92) verified the 'on the ground' relevance, importance, and realities of local interpretation of these state laws. Using a modified Delphi process, we selected 50/110 key items to include in a weighted, composite Midwifery Integration Scoring (MISS) system. Higher scores indicate greater integration of midwives across all settings. We ranked states by MISS scores; and, using reliable indicators in the CDC-Vital Statistics Database, we calculated correlation coefficients between MISS scores and maternal-newborn outcomes by state, as well as state density of midwives and place of birth. We conducted hierarchical linear regression analysis to control for confounding effects of race. RESULTS:MISS scores ranged from lowest at 17 (North Carolina) to highest at 61 (Washington), out of 100 points. Higher MISS scores were associated with significantly higher rates of spontaneous vaginal delivery, vaginal birth after cesarean, and breastfeeding, and significantly lower rates of cesarean, preterm birth, low birth weight infants, and neonatal death. MISS scores also correlated with density of midwives and access to care across birth settings. Significant differences in newborn outcomes accounted for by MISS scores persisted after controlling for proportion of African American births in each state. CONCLUSION:The MISS scoring system assesses the level of integration of midwives and evaluates regional access to high quality maternity care. In the United States, higher MISS Scores were associated with significantly higher rates of physiologic birth, less obstetric interventions, and fewer adverse neonatal outcomes.

INTRODUCTION:Annually, 2 million sports-related injuries are reported in Germany of which athletes contribute to a large proportion. Multiple sport injury prevention programs designed to decrease acute and overuse injuries in athletes have been proven effective. Yet, the programs' components, general or sports-specific, that led to these positive effects are uncertain. Despite not knowing about the superiority of sports-specific injury prevention programs, coaches and athletes alike prefer more specialized rather than generalized exercise programs. Therefore, this systematic review aimed to present the available evidence on how general and sports-specific prevention programs affect injury rates in athletes. METHODS:PubMed and Web of Science were electronically searched throughout April 2018. The inclusion criteria were publication dates Jan 2006-Dec 2017, athletes (11-45 years), exercise-based injury prevention programs and injury incidence. The methodological quality was assessed with the Cochrane Collaboration assessment tools. RESULTS:Of the initial 6619 findings, 15 studies met the inclusion criteria. In addition, 13 studies were added from reference lists and external sources making a total of 28 studies. Of which, one used sports-specific, seven general and 20 mixed prevention strategies. Twenty-four studies revealed reduced injury rates. Of the four ineffective programs, one was general and three mixed. CONCLUSION:The general and mixed programs positively affect injury rates. Sports-specific programs are uninvestigated and despite wide discussion regarding the definition, no consensus was reached. Defining such terminology and investigating the true effectiveness of such IPPs is a potential avenue for future research.

Since dietary polyphenols can have beneficial effects in prevention and treatment of cancer, we tested the hypothesis that breast cancer patients' intestinal microbiota is modulated by genistein (GE), an isoflavone found in soy, and that microbial alterations may offset the side effects brought about by chemotherapy. We demonstrated successful humanization of germ-free mice by transplanting fecal samples from breast cancer patients before and after chemotherapy. Mice were then grouped based on chemotherapy status and GE or control diet. We did not find any significant differences between pre-chemotherapy and post-chemotherapy bacterial composition and abundances. Germ-free mice on a GE diet showed differences in microbial composition as compared to mice on control diet. Four weeks after introduction of the customized GE diet, there was distinct clustering of GE-fed mice as compared to the control-fed group. In the gut microbiome of GE-treated humanized mice, there was an increase in abundance of genera Lactococcus and Eubacterium. Phylum Verrucomicrobia showed statistically significant (p = 0.02) differences in abundances between the GE-fed and control-fed groups. There was an increase in bacteria belonging to family Lachnospiraceae and Ruminococcaceae in GE-fed mice. Marked changes were observed in GE catabolism in mice humanized with fecal material from two of three patients' post-chemotherapy with complete disappearance of 4-ethylphenol and 2-(4-hydroxyphenol) propionic acid conjugates. The post-tumor samples did not show any distinct clustering of the gut microbiota between the two diet groups. There was an increase in latency of about 25% for tumor growth of the humanized mice that were on a GE diet as compared to humanized mice on a control diet. The average tumor size for the GE group was significantly decreased compared to the non-GE group. Collectively, our results suggest that the intestinal microbiota becomes altered with a GE diet before induction of tumor. Our findings indicate that GE modulates the microbiome in humanized mice that may contribute to its effects on increasing the latency of breast tumor and reducing tumor growth.

Worldwide, stillbirth is one of the leading causes of death. Altered fetal growth and placental abnormalities are the strongest and most prevalent known risk factors for stillbirth. The aim of this study was to identify patterns of association between placental abnormalities, fetal growth, and stillbirth.Population-based case-control study of all stillbirths and a representative sample of live births in 59 hospitals in 5 geographic areas in the U.S. Fetal growth abnormalities were categorized as small (90th percentile) for gestational age at death (stillbirth) or delivery (live birth) using a published algorithm. Placental examination by perinatal pathologists was performed using a standardized protocol. Data were weighted to account for the sampling design. Among 319 singleton stillbirths and 1119 singleton live births at ≥24 weeks at death or delivery respectively, 25 placental findings were investigated. Fifteen findings were significantly associated with stillbirth. Ten of the 15 were also associated with fetal growth abnormalities (single umbilical artery; velamentous insertion; terminal villous immaturity; retroplacental hematoma; parenchymal infarction; intraparenchymal thrombus; avascular villi; placental edema; placental weight; ratio birth weight/placental weight) while 5 of the 15 associated with stillbirth were not associated with fetal growth abnormalities (acute chorioamnionitis of placental membranes; acute chorioamionitis of chorionic plate; chorionic plate vascular degenerative changes; perivillous, intervillous fibrin, fibrinoid deposition; fetal vascular thrombi in the chorionic plate). Five patterns were observed: placental findings associated with (1) stillbirth but not fetal growth abnormalities; (2) fetal growth abnormalities in stillbirths only; (3) fetal growth abnormalities in live births only; (4) fetal growth abnormalities in stillbirths and live births in a similar manner; (5) a different pattern of fetal growth abnormalities in stillbirths and live births.The patterns of association between placental abnormalities, fetal growth, and stillbirth provide insights into the mechanism of impaired placental function and stillbirth. They also suggest implications for clinical care, especially for placental findings amenable to prenatal diagnosis using ultrasound that may be associated with term stillbirths.

Since 2007, mortality associated with a previously unreported haemorrhagic disease has been observed in young calves in several European countries. The syndrome, which has been named 'bovine neonatal pancytopenia' (BNP), is characterised by thrombocytopenia, leukocytopenia and a panmyelophthisis. A herd-level case-control study was conducted in four BNP affected countries (Belgium, France, Germany and the Netherlands) to identify herd management risk factors for BNP occurrence. Data were collected using structured face-to-face and telephone interviews of farm managers and their local veterinarians. In total, 363 case farms and 887 control farms were included in a matched multivariable conditional logistic regression analysis. Case-control status was strongly associated with the odds of herd level use of the vaccine PregSure® BVD (PregSure, Pfizer Animal Health) (matched adjusted odds ratio (OR) 107.2; 95% CI: 41.0-280.1). This was also the case for the practices of feeding calves colostrum from the calf's own dam (OR 2.0; 95% CI: 1.1-3.4) or feeding pooled colostrum (OR 4.1; 95% CI: 1.9-8.8). Given that the study had relatively high statistical power and represented a variety of cattle production and husbandry systems, it can be concluded with some confidence that no other herd level management factors are competent causes for a sufficient cause of BNP occurrence on herd level. It is suggested that genetic characteristics of the dams and BNP calves should be the focus of further investigations aimed at identifying the currently missing component causes that together with PregSure vaccination and colostrum feeding represent a sufficient cause for occurrence of BNP in calves.

Fishers worldwide operate in an environment of uncertainty and constant change. Their ability to manage risk associated with such uncertainty and subsequently adapt to change is largely a function of individual circumstances, including their access to different fisheries. However, explicit attention to the heterogeneity of fishers' connections to fisheries at the level of the individual has been largely ignored. We illustrate the ubiquitous nature of these connections by constructing a typology of commercial fishers in the state of Maine based on the different fisheries that fishers rely on to sustain their livelihoods and find that there are over 600 combinations. We evaluate the adaptive potential of each strategy, using a set of attributes identified by fisheries experts in the state, and find that only 12% of fishers can be classified as being well positioned to adapt in the face of changing socioeconomic and ecological conditions. Sensitivity to the uneven and heterogeneous capacity of fishers to manage risk and adapt to change is critical to devising effective management strategies that broadly support fishers. This will require greater attention to the social-ecological connectivity of fishers across different jurisdictions.

BACKGROUND:Back pain patients (BPP) show delayed muscle onset, increased co-contractions, and variability as response to quasi-static sudden trunk loading in comparison to healthy controls (H). However, it is unclear whether these results can validly be transferred to suddenly applied walking perturbations, an automated but more functional and complex movement pattern. There is an evident need to develop research-based strategies for the rehabilitation of back pain. Therefore, the investigation of differences in trunk stability between H and BPP in functional movements is of primary interest in order to define suitable intervention regimes. The purpose of this study was to analyse neuromuscular reflex activity as well as three-dimensional trunk kinematics between H and BPP during walking perturbations. METHODS:Eighty H (31m/49f;29±9yrs;174±10cm;71±13kg) and 14 BPP (6m/8f;30±8yrs;171±10cm;67±14kg) walked (1m/s) on a split-belt treadmill while 15 right-sided perturbations (belt decelerating, 40m/s2, 50ms duration; 200ms after heel contact) were randomly applied. Trunk muscle activity was assessed using a 12-lead EMG set-up. Trunk kinematics were measured using a 3-segment-model consisting of 12 markers (upper thoracic (UTA), lower thoracic (LTA), lumbar area (LA)). EMG-RMS ([%],0-200ms after perturbation) was calculated and normalized to the RMS of unperturbed gait. Latency (TON;ms) and time to maximum activity (TMAX;ms) were analysed. Total motion amplitude (ROM;[°]) and mean angle (Amean;[°]) for extension-flexion, lateral flexion and rotation were calculated (whole stride cycle; 0-200ms after perturbation) for each of the three segments during unperturbed and perturbed gait. For ROM only, perturbed was normalized to unperturbed step [%] for the whole stride as well as the 200ms after perturbation. Data were analysed descriptively followed by a student´s t-test to account for group differences. Co-contraction was analyzed between ventral and dorsal muscles (V:R) as well as side right:side left ratio (Sright:Sleft). The coefficient of variation (CV;%) was calculated (EMG-RMS;ROM) to evaluate variability between the 15 perturbations for all groups. With respect to unequal distribution of participants to groups, an additional matched-group analysis was conducted. Fourteen healthy controls out of group H were sex-, age- and anthropometrically matched (group Hmatched) to the BPP. RESULTS:No group differences were observed for EMG-RMS or CV analysis (EMG/ROM) (p>0.025). Co-contraction analysis revealed no differences for V:R and Srigth:Sleft between the groups (p>0.025). BPP showed an increased TON and TMAX, being significant for Mm. rectus abdominus (p = 0.019) and erector spinae T9/L3 (p = 0.005/p = 0.015). ROM analysis over the unperturbed stride cycle revealed no differences between groups (p>0.025). Normalization of perturbed to unperturbed step lead to significant differences for the lumbar segment (LA) in lateral flexion with BPP showing higher normalized ROM compared to Hmatched (p = 0.02). BPP showed a significant higher flexed posture (UTA (p = 0.02); LTA (p = 0.004)) during normal walking (Amean). Trunk posture (Amean) during perturbation showed higher trunk extension values in LTA segments for H/Hmatched compared to BPP (p = 0.003). Matched group (BPP vs. Hmatched) analysis did not show any systematic changes of all results between groups. CONCLUSION:BPP present impaired muscle response times and trunk posture, especially in the sagittal and transversal planes, compared to H. This could indicate reduced trunk stability and higher loading during gait perturbations.

BACKGROUND:The emergence of new strains in RNA viruses is mainly due to mutations or intra and inter-genotype homologous recombination. Non-homologous recombinations may be deleterious and are rarely detected. In previous studies, we identified HCV-1b strains bearing two tandemly repeated V3 regions in the NS5A gene without ORF disruption. This polymorphism may be associated with an unfavorable course of liver disease and possibly involved in liver carcinogenesis. Here we aimed at characterizing the origin of these mutant strains and identifying the evolutionary mechanism on which the V3 duplication relies. METHODS:Direct sequencing of the entire NS5A and E1 genes was performed on 27 mutant strains. Quasispecies analyses in consecutive samples were also performed by cloning and sequencing the NS5A gene for all mutant and wild strains. We analyzed the mutant and wild-type sequence polymorphisms using Bayesian methods to infer the evolutionary history of and the molecular mechanism leading to the duplication-like event. RESULTS:Quasispecies were entirely composed of exclusively mutant or wild-type strains respectively. Mutant quasispecies were found to have been present since contamination and had persisted for at least 10 years. This V3 duplication-like event appears to have resulted from non-homologous recombination between HCV-1b wild-type strains around 100 years ago. The association between increased liver disease severity and these HCV-1b mutants may explain their persistence in chronically infected patients. CONCLUSIONS:These results emphasize the possible consequences of non-homologous recombination in the emergence and severity of new viral diseases.

Place of birth is a known determinant of health care outcomes, interventions and costs. Many studies have examined the maternal and perinatal outcomes when women plan to give birth in hospitals compared with births in birth centres or at home. However, these studies vary substantially in rigour; assessing their quality is challenging. Existing research appraisal tools do not always capture important elements of study design that are critical when comparing outcomes by planned place of birth. To address this deficiency, we aimed to develop a reliable instrument to rate the quality of primary research on maternal and newborn outcomes by place of birth.The instrument development process involved five phases: 1) generation of items and a weighted scoring system; 2) content validation via a quantitative survey and a modified Delphi process with an international, multi-disciplinary panel of experts; 3) inter-rater consistency; 4) alignment with established research appraisal tools; and 5) pilot-testing of instrument usability.A Birth Place Research Quality Index (ResQu Index) was developed comprising 27 scored items that are summed to generate a weighted composite score out of 100 for studies comparing planned place of birth. Scale content validation indices were .89 for clarity, .94 for relevance and .90 for importance. The Index demonstrated substantial inter-rater consistency; pilot-testing confirmed feasibility and user-friendliness.The ResQu Index is a reliable instrument to evaluate the quality of design, methods and interpretation of reported outcomes from research about place of birth. Higher-scoring studies have greater potential to inform evidence-based selection of birth place by clinicians, policy makers, and women and their families. The Index can also guide the design of future research on place of birth.

OBJECTIVE:To develop and validate a new instrument that assesses women's autonomy and role in decision making during maternity care. DESIGN:Through a community-based participatory research process, service users designed, content validated, and administered a cross-sectional quantitative survey, including 31 items on the experience of decision-making. SETTING AND PARTICIPANTS:Pregnancy experiences (n = 2514) were reported by 1672 women who saw a single type of primary maternity care provider in British Columbia. They described care by a midwife, family physician or obstetrician during 1, 2 or 3 maternity care cycles. We conducted psychometric testing in three separate samples. MAIN OUTCOME MEASURES:We assessed reliability, item-to-total correlations, and the factor structure of the The Mothers' Autonomy in Decision Making (MADM) scale. We report MADM scores by care provider type, length of prenatal appointments, preferences for role in decision-making, and satisfaction with experience of decision-making. RESULTS:The MADM scale measures a single construct: autonomy in decision-making during maternity care. Cronbach alphas for the scale exceeded 0.90 for all samples and all provider groups. All item-to-total correlations were replicable across three samples and exceeded 0.7. Eigenvalue and scree plots exhibited a clear 90-degree angle, and factor analysis generated a one factor scale. MADM median scores were highest among women who were cared for by midwives, and 10 or more points lower for those who saw physicians. Increased time for prenatal appointments was associated with higher scale scores, and there were significant differences between providers with respect to average time spent in prenatal appointments. Midwifery care was associated with higher MADM scores, even during short prenatal appointments (

Nanoparticles are ubiquitous in the environment. They originate from anthropogenic or natural sources or they are intentionally produced for different purposes. There exist manifold applications of nanoparticles in modern life leading unavoidably to a confrontation and interaction between nanomaterial and living organisms. Based on their wide distribution tending to increase steadily, the influence of particles based on silica and silver, exhibiting nominal sizes between 0.65 nm and 200 nm, on the physiology of the mycotoxigenic filamentous fungus Penicillium verrucosum was analyzed. The applied concentration and time-point, the size and the chemical composition of the particles was shown to have a strong influence on growth and mycotoxin biosynthesis. On microscopic scale it could be shown that silver nanoparticles attach to the mycelial surface. Moreover, silver nanoparticles with 0.65 nm and 5 nm in size were shown to internalize within the cell, form agglomerates in the cytoplasm and associate to cell organelles.

Coccolithophores are a vital part of oceanic phytoplankton assemblages that produce organic matter and calcium carbonate (CaCO3) containing traces of other elements (i.e. Sr and Mg). Their associated carbon export from the euphotic zone to the oceans' interior plays a crucial role in CO2 feedback mechanisms and biogeochemical cycles. The coccolithophore Emiliania huxleyi has been widely studied as a model organism to understand physiological, biogeochemical, and ecological processes in marine sciences. Here, we show the inter-strain variability in physiological and biogeochemical traits in 13 strains of E. huxleyi from various biogeographical provinces obtained from culture collections commonly used in the literature. Our results demonstrate that inter-strain genetic variability has greater potential to induce larger phenotypic differences than the phenotypic plasticity of single strains cultured under a broad range of variable environmental conditions. The range of variation found in physiological parameters and calcite Sr:Ca highlights the need to reconsider phenotypic variability in paleoproxy calibrations and model parameterizations to adequately translate findings from single strain laboratory experiments to the real ocean.

BACKGROUND AND PURPOSE:Ischemic stroke provokes severe brain damage and remains a predominant disease in industrialized countries. The coagulation factor XII (FXII)-driven contact activation system plays a central, but not yet fully defined pathogenic role in stroke development. Here, we investigated the efficacy of the FXIIa inhibitor rHA-Infestin-4 in a rat model of ischemic stroke using both a prophylactic and a therapeutic approach. METHODS:For prophylactic treatment, animals were treated intravenously with 100 mg/kg rHA-Infestin-4 or an equal volume of saline 15 min prior to transient middle cerebral artery occlusion (tMCAO) of 90 min. For therapeutic treatment, 100 mg/kg rHA-Infestin-4, or an equal volume of saline, was administered directly after the start of reperfusion. At 24 h after tMCAO, rats were tested for neurological deficits and blood was drawn for coagulation assays. Finally, brains were removed and analyzed for infarct area and edema formation. RESULTS:Within prophylactic rHA-Infestin-4 treatment, infarct areas and brain edema formation were reduced accompanied by better neurological scores and survival compared to controls. Following therapeutic treatment, neurological outcome and survival were still improved although overall effects were less pronounced compared to prophylaxis. CONCLUSIONS:With regard to the central role of the FXII-driven contact activation system in ischemic stroke, inhibition of FXIIa may represent a new and promising treatment approach to prevent cerebral ischemia/reperfusion injury.

Parastagonospora nodorum, the causal agent of Septoria nodorum blotch (SNB), is an economically important pathogen of wheat (Triticum spp.), and a model for the study of necrotrophic pathology and genome evolution. The reference P. nodorum strain SN15 was the first Dothideomycete with a published genome sequence, and has been used as the basis for comparison within and between species. Here we present an updated reference genome assembly with corrections of SNP and indel errors in the underlying genome assembly from deep resequencing data as well as extensive manual annotation of gene models using transcriptomic and proteomic sources of evidence (https://github.com/robsyme/Parastagonospora_nodorum_SN15). The updated assembly and annotation includes 8,366 genes with modified protein sequence and 866 new genes. This study shows the benefits of using a wide variety of experimental methods allied to expert curation to generate a reliable set of gene models.

PURPOSE:Intensity modulated radiation therapy (IMRT) of head and neck tumors allows a precise conformation of the high-dose region to clinical target volumes (CTVs) while respecting dose limits to organs a risk (OARs). Accurate patient setup reduces translational and rotational deviations between therapy planning and therapy delivery days. However, uncertainties in the shape of the CTV and OARs due to e.g. small pose variations in the highly deformable anatomy of the head and neck region can still compromise the dose conformation. Routinely applied safety margins around the CTV cause higher dose deposition in adjacent healthy tissue and should be kept as small as possible. MATERIALS AND METHODS:In this work we evaluate and compare three approaches for margin generation 1) a clinically used approach with a constant isotropic 3 mm margin, 2) a previously proposed approach adopting a spatial model of the patient and 3) a newly developed approach adopting a biomechanical model of the patient. All approaches are retrospectively evaluated using a large patient cohort of over 500 fraction control CT images with heterogeneous pose changes. Automatic methods for finding landmark positions in the control CT images are combined with a patient specific biomechanical finite element model to evaluate the CTV deformation. RESULTS:The applied methods for deformation modeling show that the pose changes cause deformations in the target region with a mean motion magnitude of 1.80 mm. We found that the CTV size can be reduced by both variable margin approaches by 15.6% and 13.3% respectively, while maintaining the CTV coverage. With approach 3 an increase of target coverage was obtained. CONCLUSION:Variable margins increase target coverage, reduce risk to OARs and improve healthy tissue sparing at the same time.

Serotonin (5-hydroxytryptamin, 5-HT) is an indolamine platelet agonist, biochemically derived from tryptophan. 5-HT is secreted from the enterochromaffin cells into the gastrointestinal tract and blood. Blood 5-HT has been proposed to regulate hemostasis by acting as a vasoconstrictor and by triggering platelet signaling through 5-HT receptor 2A (5HTR2A). Although platelets do not synthetize 5-HT, they take 5-HT up from the blood and store it in their dense granules which are secreted upon platelet activation.To identify the molecular composite of the 5-HT uptake system in platelets and elucidate the role of platelet released 5-HT in thrombosis and ischemic stroke.5-HT transporter knockout mice (5Htt-/-) were analyzed in different in vitro and in vivo assays and in a model of ischemic stroke.In 5Htt-/- platelets, 5-HT uptake from the blood was completely abolished and agonist-induced Ca2+ influx through store operated Ca2+ entry (SOCE), integrin activation, degranulation and aggregation responses to glycoprotein VI (GPVI) and C-type lectin-like receptor 2 (CLEC-2) were reduced. These observed in vitro defects in 5Htt-/- platelets could be normalized by the addition of exogenous 5-HT. Moreover, reduced 5-HT levels in the plasma, an increased bleeding time and the formation of unstable thrombi were observed ex vivo under flow and in vivo in the abdominal aorta and carotid artery of 5Htt-/- mice. Surprisingly, in the transient middle cerebral artery occlusion (tMCAO) model of ischemic stroke 5Htt-/- mice showed nearly normal infarct volume and the neurological outcome was comparable to control mice.Although secreted platelet 5-HT does not appear to play a crucial role in the development of reperfusion injury after stroke, it is essential to amplify the second phase of platelet activation through SOCE and plays an important role in thrombus stabilization.

In forests, the vulnerable seedling stage is largely influenced by the canopy, which modifies the surrounding environment. Consequently, any alteration in the characteristics of the canopy, such as those promoted by forest dieback, might impact regeneration dynamics. Our work analyzes the interaction between canopy neighbors and seedlings in Mediterranean forests affected by the decline of their dominant species (Quercus suber). Our objective was to understand how the impacts of neighbor trees and shrubs on recruitment could affect future dynamics of these declining forests. Seeds of the three dominant tree species (Quercus suber, Olea europaea and Quercus canariensis) were sown in six sites during two consecutive years. Using a spatially-explicit, neighborhood approach we developed models that explained the observed spatial variation in seedling emergence, survival, growth and photochemical efficiency as a function of the size, identity, health, abundance and distribution of adult trees and shrubs in the neighborhood. We found strong neighborhood effects for all the performance estimators, particularly seedling emergence and survival. Tree neighbors positively affected emergence, independently of species identity or health. Alternatively, seedling survival was much lower in neighborhoods dominated by defoliated and dead Q. suber trees than in neighborhoods dominated by healthy trees. For the two oak species, these negative effects were consistent over the three years of the experimental seedlings. These results indicate that ongoing changes in species' relative abundance and canopy trees' health might alter the successional trajectories of Mediterranean oak-forests through neighbor-specific impacts on seedlings. The recruitment failure of dominant late-successional oaks in the gaps opened after Q. suber death would indirectly favor the establishment of other coexisting woody species, such as drought-tolerant shrubs. This could lead current forests to shift into open systems with lower tree cover. Adult canopy decline would therefore represent an additional factor threatening the recruitment of Quercus forests worldwide.

To identify early markers of necrotizing enterocolitis (NEC), we hypothesized that continuous abdominal near-infrared spectroscopy (A-NIRS) measurement of splanchnic tissue oxygen saturation and intermittent plasma intestinal fatty-acid binding protein (pI-FABP) measured every 6 hours can detect NEC prior to onset of clinical symptoms. Premature piglets received parenteral nutrition for 48-hours after delivery, followed by enteral feeds every three hours until death or euthanasia at 96-hours. Continuous A-NIRS, systemic oxygen saturation (SpO2), and heart rate were measured while monitoring for clinical signs of NEC. Blood samples obtained at 6-hour intervals were used to determine pI-FABP levels by ELISA. Piglets were classified as fulminant-NEC (f-NEC), non-fulminant-NEC (nf-NEC) and No-NEC according to severity of clinical and histologic features. Of 38 piglets, 37% (n=14) developed nf-NEC, 18% (n=7) developed f-NEC and 45% (n=17) had No-NEC. There were significant differences in baseline heart rate (p=0.008), SpO2 (p0.25ng/mL identified animals with NEC (68% sensitivity and 90% specificity). NIRS is a real-time, non-invasive tool that can serve as a diagnostic modality for NEC. In premature piglets, low A-NIRS in the early neonatal period and increased variability during initial feeds are highly predictive of NEC, which is then confirmed by rising plasma I-FABP levels. These modalities may help identify neonates with NEC prior to clinical manifestations of disease.

Reactivation of fetal gene expression patterns has been implicated in common cardiac diseases in adult life including left ventricular (LV) hypertrophy (LVH) in arterial hypertension. Thus, increased wall stress and neurohumoral activation are discussed to induce the return to expression of fetal genes after birth in LVH. We therefore aimed to identify novel potential candidates for LVH by analyzing fetal-adult cardiac gene expression in a genetic rat model of hypertension, i.e. the stroke-prone spontaneously hypertensive rat (SHRSP). To this end we performed genome-wide transcriptome analysis in SHRSP to identify differences in expression patterns between day 20 of fetal development (E20) and adult animals in week 14 in comparison to a normotensive rat strain with contrasting low LV mass, i.e. Fischer (F344). 15232 probes were detected as expressed in LV tissue obtained from rats at E20 and week 14 (p < 0.05) and subsequently screened for differential expression. We identified 24 genes with SHRSP specific up-regulation and 21 genes with down-regulation as compared to F344. Further bioinformatic analysis presented Efcab6 as a new candidate for LVH that showed only in the hypertensive SHRSP rat differential expression during development (logFC = 2.41, p < 0.001) and was significantly higher expressed in adult SHRSP rats compared with adult F344 (+ 76%) and adult normotensive Wistar-Kyoto rats (+ 82%). Thus, it represents an interesting new target for further functional analyses and the elucidation of mechanisms leading to LVH. Here we report a new approach to identify candidate genes for cardiac hypertrophy by combining the analysis of gene expression differences between strains with a contrasting cardiac phenotype with a comparison of fetal-adult cardiac expression patterns.

The main objective of this study was to determine growth, yield and fruit quality of grapevines under organic and biodynamic management in relation to integrated viticultural practices. Furthermore, the mechanisms for the observed changes in growth, yield and fruit quality were investigated by determining nutrient status, physiological performance of the plants and disease incidence on bunches in three consecutive growing seasons. A field trial (Vitis vinifera L. cv. Riesling) was set up at Hochschule Geisenheim University, Germany. The integrated treatment was managed according to the code of good practice. Organic and biodynamic plots were managed according to Regulation (EC) No 834/2007 and Regulation (EC) No 889/2008 and according to ECOVIN- and Demeter-Standards, respectively. The growth and yield of the grapevines differed strongly among the different management systems, whereas fruit quality was not affected by the management system. The organic and the biodynamic treatments showed significantly lower growth and yield in comparison to the integrated treatment. The physiological performance was significantly lower in the organic and the biodynamic systems, which may account for differences in growth and cluster weight and might therefore induce lower yields of the respective treatments. Soil management and fertilization strategy could be responsible factors for these changes. Yields of the organic and the biodynamic treatments partially decreased due to higher disease incidence of downy mildew. The organic and the biodynamic plant protection strategies that exclude the use of synthetic fungicides are likely to induce higher disease incidence and might partially account for differences in the nutrient status of vines under organic and biodynamic management. Use of the biodynamic preparations had little influence on vine growth and yield. Due to the investigation of important parameters that induce changes especially in growth and yield of grapevines under organic and biodynamic management the study can potentially provide guidance for defining more effective farming systems.

Recent studies reported altered DNA methylation in failing human hearts. This may suggest a role for de novo DNA methylation in the development of heart failure. Here, we tested whether cardiomyocyte-specific loss of de novo DNA methyltransferases Dnmt3a and Dnmt3b altered cardiac function and remodeling after chronic left ventricular pressure overload.Mice with specific ablation of Dnmt3a and Dnmt3b expression in cardiomyocytes were generated by crossing floxed Dnmt3afl and Dnmt3bfl alleles with mice expressing Cre recombinase under control of the atrial myosin light chain gene promoter. The efficacy of combined Dnmt3a/3b ablation (DKO) was characterized on cardiomyocyte-specific genomic DNA and mRNA levels. Cardiac phenotyping was carried out without (sham) or with left ventricular pressure overload induced by transverse aortic constriction (TAC). Under similar conditions, cardiac genome-wide transcriptional profiling was performed and DNA methylation levels of promoters of differentially regulated genes were assessed by pyrosequencing.DKO cardiomyocytes showed virtual absence of targeted Dnmt3a and Dnmt3b mRNA transcripts. Cardiac phenotyping revealed no significant differences between DKO and control mice under sham and TAC conditions. Transcriptome analyses identified upregulation of 44 and downregulation of 9 genes in DKO as compared with control sham mice. TAC mice showed similar changes with substantial overlap of regulated genes compared to sham. Promoters of upregulated genes were largely unmethylated in DKO compared to control mice.The absence of cardiac pathology in the presence of the predicted molecular phenotype suggests that de novo DNA methylation in cardiomyocytes is dispensable for adaptive mechanisms after chronic cardiac pressure overload.

The financial crisis illustrated the need for a functional understanding of systemic risk in strongly interconnected financial structures. Dynamic processes on complex networks being intrinsically difficult to model analytically, most recent studies of this problem have relied on numerical simulations. Here we report analytical results in a network model of interbank lending based on directly relevant financial parameters, such as interest rates and leverage ratios. We obtain a closed-form formula for the "critical degree" (the number of creditors per bank below which an individual shock can propagate throughout the network), and relate failures distributions to network topologies, in particular scalefree ones. Our criterion for the onset of contagion turns out to be isomorphic to the condition for cooperation to evolve on graphs and social networks, as recently formulated in evolutionary game theory. This remarkable connection supports recent calls for a methodological rapprochement between finance and ecology.

Vertebrate innate immunity is the first line of defense against an invading pathogen and has long been assumed to be largely unspecific with respect to parasite/pathogen species. However, recent phenotypic evidence suggests that immunogenetic variation, i.e. allelic variability in genes associated with the immune system, results in host-parasite genotype-by-genotype interactions and thus specific innate immune responses. Immunogenetic variation is common in all vertebrate taxa and this reflects an effective immunological function in complex environments. However, the underlying variability in host gene expression patterns as response of innate immunity to within-species genetic diversity of macroparasites in vertebrates is unknown. We hypothesized that intra-specific variation among parasite genotypes must be reflected in host gene expression patterns. Here we used high-throughput RNA-sequencing to examine the effect of parasite genotypes on gene expression patterns of a vertebrate host, the three-spined stickleback (Gasterosteus aculeatus). By infecting naïve fish with distinct trematode genotypes of the species Diplostomum pseudospathaceum we show that gene activity of innate immunity in three-spined sticklebacks depended on the identity of an infecting macroparasite genotype. In addition to a suite of genes indicative for a general response against the trematode we also find parasite-strain specific gene expression, in particular in the complement system genes, despite similar infection rates of single clone treatments. The observed discrepancy between infection rates and gene expression indicates the presence of alternative pathways which execute similar functions. This suggests that the innate immune system can induce redundant responses specific to parasite genotypes.

OBJECTIVE: We assessed trends in the proportion of transmitted (TDR) and acquired (ADR) HIV drug resistance and associated mutations between 2001 and 2011 in the German ClinSurv-HIV Drug Resistance Study. METHOD: The German ClinSurv-HIV Drug Resistance Study is a subset of the German ClinSurv-HIV Cohort. For the ClinSurv-HIV Drug Resistance Study all available sequences isolated from patients in five study centres of the long term observational ClinSurv-HIV Cohort were included. TDR was estimated using the first viral sequence of antiretroviral treatment (ART) naïve patients. One HIV sequence/patient/year of ART experienced patients was considered to estimate the proportion of ADR. Trends in the proportion of HIV drug resistance were calculated by logistic regression. RESULTS: 9,528 patients were included into the analysis. HIV-sequences of antiretroviral naïve and treatment experienced patients were available from 34% (3,267/9,528) of patients. The proportion of TDR over time was stable at 10.4% (95% CI 9.1-11.8; p for trend = 0.6; 2001-2011). The proportion of ADR among all treated patients was 16%, whereas it was high among those with available HIV genotypic resistance test (64%; 1,310/2,049 sequences; 95% CI 62-66) but declined significantly over time (OR 0.8; 95% CI 0.77-0.83; p for trend

Glioma is the most common form of primary brain tumor. Demographically, the risk of occurrence increases until old age. Here we present a novel computational model to reproduce the probability of glioma incidence across the lifespan. Previous mathematical models explaining glioma incidence are framed in a rather abstract way, and do not directly relate to empirical findings. To decrease this gap between theory and experimental observations, we incorporate recent data on cellular and molecular factors underlying gliomagenesis. Since evidence implicates the adult neural stem cell as the likely cell-of-origin of glioma, we have incorporated empirically-determined estimates of neural stem cell number, cell division rate, mutation rate and oncogenic potential into our model. We demonstrate that our model yields results which match actual demographic data in the human population. In particular, this model accounts for the observed peak incidence of glioma at approximately 80 years of age, without the need to assert differential susceptibility throughout the population. Overall, our model supports the hypothesis that glioma is caused by randomly-occurring oncogenic mutations within the neural stem cell population. Based on this model, we assess the influence of the (experimentally indicated) decrease in the number of neural stem cells and increase of cell division rate during aging. Our model provides multiple testable predictions, and suggests that different temporal sequences of oncogenic mutations can lead to tumorigenesis. Finally, we conclude that four or five oncogenic mutations are sufficient for the formation of glioma.

It is commonly assumed that the colonization of restored river reaches by fish depends on the regional species pools; however, quantifications of the relationship between the composition of the regional species pool and restoration outcome are lacking. We analyzed data from 18 German river restoration projects and adjacent river reaches constituting the regional species pools of the restored reaches. We found that the ability of statistical models to describe the fish assemblages established in the restored reaches was greater when these models were based on 'biotic' variables relating to the regional species pool and the ecological traits of species rather than on 'abiotic' variables relating to the hydromorphological habitat structure of the restored habitats and descriptors of the restoration projects. For species presence in restored reaches, 'biotic' variables explained 34% of variability, with the occurrence rate of a species in the regional species pool being the most important variable, while 'abiotic' variables explained only the negligible amount of 2% of variability. For fish density in restored reaches, about twice the amount of variability was explained by 'biotic' (38%) compared to 'abiotic' (21%) variables, with species density in the regional species pool being most important. These results indicate that the colonization of restored river reaches by fish is largely determined by the assemblages in the surrounding species pool. Knowledge of species presence and abundance in the regional species pool can be used to estimate the likelihood of fish species becoming established in restored reaches.

Enteral formula feeding is a risk factor for necrotizing enterocolitis (NEC) in premature infants, yet studies are conflicting regarding the safest timing for introduction and advancement of feeds. Our aim was to test the effects of early vs. late initiation and abrupt vs. gradual advancement of enteral feeding of an intact vs. hydrolyzed protein formula on NEC incidence and severity in preterm pigs. In Experiment 1, preterm pigs received total parenteral nutrition (TPN) at birth with abrupt initiation of enteral formula feeds (50% full intake) on d of life (DOL) 2 (EA) or 5 (LA) while PN continued. Pigs were also fed formula containing either intact or hydrolyzed protein. In Experiment 2, preterm pigs received TPN at birth with enteral, hydrolyzed-protein formula feeds introduced on DOL 2 either abruptly (EA; 50% full feeds) or gradually (EG; 10-50% full feeds over 5 d) while PN continued. NEC incidence and severity were assessed based on macroscopic and histological scoring. In Experiment 1, NEC incidence (41% vs. 70%, P

BACKGROUND AND PURPOSE: In animal models, von Willebrand factor (VWF) is involved in thrombus formation and propagation of ischemic stroke. However, the pathophysiological relevance of this molecule in humans, and its potential use as a biomarker for the risk and severity of ischemic stroke remains unclear. This study had two aims: to identify predictors of altered VWF levels and to examine whether VWF levels differ between acute cerebrovascular events and chronic cerebrovascular disease (CCD). METHODS: A case-control study was undertaken between 2010 and 2013 at our University clinic. In total, 116 patients with acute ischemic stroke (AIS) or transitory ischemic attack (TIA), 117 patients with CCD, and 104 healthy volunteers (HV) were included. Blood was taken at days 0, 1, and 3 in patients with AIS or TIA, and once in CCD patients and HV. VWF serum levels were measured and correlated with demographic and clinical parameters by multivariate linear regression and ANOVA. RESULTS: Patients with CCD (158 ± 46%) had significantly higher VWF levels than HV (113 ± 36%, P

Protein kinase D isoenzymes (PKDs, Prkds) are serine threonine kinases that belong to the CAMK superfamily. PKD1 is expressed in endothelial cells and is a major mediator of biological responses downstream of the VEGFRs that are relevant for angiogenesis such as endothelial cell migration, proliferation and tubulogenesis in vitro. PKDs also play a critical role in tumor development and progression, including tumor angiogenesis. However, given the plethora of signaling modules that drive angiogenesis, the precise role of PKD1 in both physiological and tumor angiogenesis in vivo has not been worked out so far. This study aimed at dissecting the contribution of PKD1 to physiological blood vessel formation, PKD1 was found to be widely expressed during zebrafish development. As far as physiological angiogenesis was concerned, morpholino-based silencing of PKD1 expression moderately reduced the formation of the intersomitic vessels and the dorsal longitudinal anastomotic vessel in tg(fli1:EGFP) zebrafish. In addition, silencing of PKD1 resulted in reduced formation of the parachordal lymphangioblasts that serves as a precursor for the developing thoracic duct. Interestingly, tumor angiogenesis was completely abolished in PKD1 morphants using the zebrafish/tumor xenograft angiogenesis assay. Our data in zebrafish demonstrate that PKD1 contributes to the regulation of physiological angiogenesis and lymphangiogenesis during zebrafish development and is essential for tumor angiogenesis.

Fibrinogen like protein 1(Fgl1) is a secreted protein with mitogenic activity on primary hepatocytes. Fgl1 is expressed in the liver and its expression is enhanced following acute liver injury. In animals with acute liver failure, administration of recombinant Fgl1 results in decreased mortality supporting the notion that Fgl1 stimulates hepatocyte proliferation and/or protects hepatocytes from injury. However, because Fgl1 is secreted and detected in the plasma, it is possible that the role of Fgl1 extends far beyond its effect on hepatocytes. In this study, we show that Fgl1 is additionally expressed in brown adipose tissue. We find that signals elaborated following liver injury also enhance the expression of Fgl1 in brown adipose tissue suggesting that there is a cross talk between the injured liver and adipose tissues. To identify extra hepatic effects, we generated Fgl1 deficient mice. These mice exhibit a phenotype suggestive of a global metabolic defect: Fgl1 null mice are heavier than wild type mates, have abnormal plasma lipid profiles, fasting hyperglycemia with enhanced gluconeogenesis and exhibit differences in white and brown adipose tissue morphology when compared to wild types. Because Fgl1 shares structural similarity to Angiopoietin like factors 2, 3, 4 and 6 which regulate lipid metabolism and energy utilization, we postulate that Fgl1 is a member of an emerging group of proteins with key roles in metabolism and liver regeneration.

The poor response to the combined antiviral therapy of pegylated alfa-interferon and ribavarin for hepatitis C virus (HCV) infection may be linked to mutations in the viral envelope gene E1E2 (env), which can result in escape from the immune response and higher efficacy of viral entry. Mutations that result in failure of therapy most likely require compensatory mutations to achieve sufficient change in envelope structure and function. Compensatory mutations were investigated by determining positions in the E1E2 gene where amino acids (aa) covaried across groups of individuals. We assessed networks of covarying positions in E1E2 sequences that differentiated sustained virological response (SVR) from non-response (NR) in 43 genotype 1a (17 SVR), and 49 genotype 1b (25 SVR) chronically HCV-infected individuals. Binary integer programming over covariance networks was used to extract aa combinations that differed between response groups. Genotype 1a E1E2 sequences exhibited higher degrees of covariance and clustered into 3 main groups while 1b sequences exhibited no clustering. Between 5 and 9 aa pairs were required to separate SVR from NR in each genotype. aa in hypervariable region 1 were 6 times more likely than chance to occur in the optimal networks. The pair 531-626 (EI) appeared frequently in the optimal networks and was present in 6 of 9 NR in one of the 1a clusters. The most frequent pairs representing SVR were 431-481 (EE), 500-522 (QA) in 1a, and 407-434 (AQ) in 1b. Optimal networks based on covarying aa pairs in HCV envelope can indicate features that are associated with failure or success to antiviral therapy.