Rotation and activity of pre-main-sequence stars

We present a study of rotation (vsini) and chromospheric activity (Halpha EW) based on an extensive set of high-resolution optical spectra obtained with MIKE on the 6.5m Magellan Clay telescope. Our targets are 74 F-M dwarfs in the young stellar associations Eta Cha, TW Hydrae, Beta Pic, and Tuc-Hor, spanning ages from 6 to 30 Myr. While the Halpha EW for most F and G stars are consistent with pure photospheric absorption, most K and M stars show chromospheric emission. By comparing Halpha EW in our sample to results in the literature, we see a clear evolutionary sequence: Chromospheric activity declines steadily from the T Tauri phase to the main sequence. Using activity as an age indicator, we find a plausible age range for the Tuc-Hor association of 10-40 Myr. Between 5 and 30 Myr, we do not see evidence for rotational braking in the total sample, thus angular momentum is conserved, in contrast to younger stars. This difference indicates a change in the rotational regulation at 5-10 Myr, possibly because disk braking cannot operate longer than typical disk lifetimes, allowing the objects to spin up. The rotation-activity relation is flat in our sample; in contrast to main-sequence stars, there is no linear correlation for slow rotators. We argue that this is because young stars generate their magnetic fields in a fundamentally different way from main-sequence stars, and not just the result of a saturated solar-type dynamo. By comparing our rotational velocities with published rotation periods for a subset of stars, we determine ages of 13 (7-20) Myr and 9 (7-17} Myr for the Eta Cha and TWA associations, respectively, consistent with previous estimates. Thus we conclude that stellar radii from evolutionary models by Baraffe et al. (1998) are in agreement with the observed radii within +-15%. (abridged)Comment: 40 pages, 8 figures, ApJ, in pres

Structure of S. aureus HPPK and discovery of a new inhibitor

The first structural and biophysical data on the folate pathway enzyme and drug target, 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase (HPPK), from the pathogenic bacterium Staphylococcus aureus is presented. HPPK is the second essential enzyme in the folate biosynthesis pathway, responsible for catalysing pyrophosphoryl transfer from cofactor (ATP) to the substrate (6-hydroxymethyl- 7,8-dihydropterin, HMDP). In-silico screening led to the discovery of a substrate competitive inhibitor, San1, which was subsequently co-crystallised with HPPK. A 1.65 Å resolution x-ray structure showed this to bind at the pterin site sharing many of the key intermolecular interactions of the substrate. ITC and SPR measurements yielded an equilibrium binding constant, Kd, of ~13 μM for San1. An IC50 of ~12 μM was determined by means of a new convenient tri-enzyme-coupled spectrophotometric assay. ITC and SPR further showed that the San1 inhibitor has no requirement for magnesium or ATP cofactor for competitive binding to the substrate site. According to 15N heteronuclear NMR measurements, the fast motion of the pterin loop (L2) is partially dampened in the ternary complex between SaHPPK, HMDP and , -methylene adenosine 5-triphosphate (AMPCPP), but the ATP loop (L3) remains mobile on the μs timescale. In contrast, for the SaHPPK/San1/AMPCPP ternary complex, loop L2 becomes rigid on the fast timescale and loop L3 becomes more ordered which are supported by a large entropic penalty associated with San1 binding as revealed by ITC. Backbone assignments and chemical shift perturbations implicate the sulphur in San1 as a likely important loop L2/L3 stabilizing mediato

Impact of co-morbid burden on mortality in patients with coronary heart disease, heart failure, and cerebrovascular accident: a systematic review and meta-analysis.

Aims: We sought to investigate the prognostic impact of co-morbid burden as defined by the Charlson Co-morbidity Index (CCI) in patients with a range of prevalent cardiovascular diseases. Methods and results: We searched MEDLINE and EMBASE to identify studies that evaluated the impact of CCI on mortality in patients with cardiovascular disease. A random-effects meta-analysis was undertaken to evaluate the impact of CCI on mortality in patients with coronary heart disease (CHD), heart failure (HF), and cerebrovascular accident (CVA). A total of 11 studies of acute coronary syndrome (ACS), 2 stable coronary disease, 5 percutaneous coronary intervention (PCI), 13 HF, and 4 CVA met the inclusion criteria. An increase in CCI score per point was significantly associated with a greater risk of mortality in patients with ACS [pooled relative risk ratio (RR) 1.33; 95% CI 1.15-1.54], PCI (RR 1.21; 95% CI 1.12-1.31), stable coronary artery disease (RR 1.38; 95% CI 1.29-1.48), and HF (RR 1.21; 95% CI 1.13-1.29), but not CVA. A CCI score of >2 significantly increased the risk of mortality in ACS (RR 2.52; 95% CI 1.58-4.04), PCI (RR 3.36; 95% CI 2.14-5.29), HF (RR 1.76; 95% CI 1.65-1.87), and CVA (RR 3.80; 95% CI 1.20-12.01). Conclusion: Increasing co-morbid burden as defined by CCI is associated with a significant increase in risk of mortality in patients with underlying CHD, HF, and CVA. CCI provides a simple way of predicting adverse outcomes in patients with cardiovascular disease and should be incorporated into decision-making processes when counselling patients

Can cutaneous telangiectasiae as late normal-tissue injury predict cardiovascular disease in women receiving radiotherapy for breast cancer?

Background: Overall, ~5% of patients show late normal-tissue damage after radiotherapy with a smaller number having a risk of radiation-induced heart disease. Although the data are conflicting, large studies have shown increased risks of cardiovascular disease (CVD) for irradiated patients compared with non-irradiated ones, or for those treated to the left breast or chest wall compared with those treated to the right. Cutaneous telangiectasiae as late normal-tissue injury have so far only been regarded as a cosmetic burden. Methods: The relationship between late normal-tissue radiation injury phenotypes in 149 irradiated breast cancer patients and the presence of cardiovascular disease were examined. Results: A statistically significant association between the presence of skin telangiectasiae and the long-term risk of CVD was shown in these patients (P=0.017; Fisher's exact test). Interpretation: This association may represent initial evidence that telangiectasiae can be used as a marker of future radiation-induced cardiac complications. It could also suggest a common biological pathway for the development of both telangiectasiae and CVD on the basis of a genetically predisposed endothelium. To our knowledge this is the first reported study looking at this association

Prognosis research strategy (PROGRESS) 1: a framework for researching clinical outcomes.

The PROGRESS series (www.progress-partnership.org) sets out a framework of four interlinked prognosis research themes and provides examples from several disease fields to show why evidence from prognosis research is crucial to inform all points in the translation of biomedical and health related research into better patient outcomes. Recommendations are made in each of the four papers to improve current research standards What is prognosis research? Prognosis research seeks to understand and improve future outcomes in people with a given disease or health condition. However, there is increasing evidence that prognosis research standards need to be improved Why is prognosis research important? More people now live with disease and conditions that impair health than at any other time in history; prognosis research provides crucial evidence for translating findings from the laboratory to humans, and from clinical research to clinical practice This first article introduces the framework of four interlinked prognosis research themes and then focuses on the first of the themes - fundamental prognosis research, studies that aim to describe and explain future outcomes in relation to current diagnostic and treatment practices, often in relation to quality of care Fundamental prognosis research provides evidence informing healthcare and public health policy, the design and interpretation of randomised trials, and the impact of diagnostic tests on future outcome. It can inform new definitions of disease, may identify unanticipated benefits or harms of interventions, and clarify where new interventions are required to improve prognosis

Development and validation of prediction models to estimate risk of primary total hip and knee replacements using data from the UK : two prospective open cohorts using the UK Clinical Practice Research Datalink

Altres ajuts: This study was funded by NIHR School for Primary Care Research Funding Round 9 (Project No: 258) and by Public Health England. CDM is funded by the NIHR Collaborations for Leadership in Applied Health Research and Care West Midlands, the NIHR School for Primary Care Research and a NIHR Research Professorship in General Practice (NIHR-RP-2014-04-026). JE is a NIHR Academic Clinical Lecturer. The views expressed in this paper are those of the author(s) and not necessarily those of the NHS, the NIHR, Public Health England, or the Department of Health. This research is funded by the National Institute for Health Research School for Primary Care Research (NIHR SPCR).The ability to efficiently and accurately predict future risk of primary total hip and knee replacement (THR/TKR) in earlier stages of osteoarthritis (OA) has potentially important applications. We aimed to develop and validate two models to estimate an individual's risk of primary THR and TKR in patients newly presenting to primary care. We identified two cohorts of patients aged ≥40 years newly consulting hip pain/OA and knee pain/OA in the Clinical Practice Research Datalink. Candidate predictors were identified by systematic review, novel hypothesis-free 'Record-Wide Association Study' with replication, and panel consensus. Cox proportional hazards models accounting for competing risk of death were applied to derive risk algorithms for THR and TKR. Internal-external cross-validation (IECV) was then applied over geographical regions to validate two models. 45 predictors for THR and 53 for TKR were identified, reviewed and selected by the panel. 301 052 and 416 030 patients newly consulting between 1992 and 2015 were identified in the hip and knee cohorts, respectively (median follow-up 6 years). The resultant model C-statistics is 0.73 (0.72, 0.73) and 0.79 (0.78, 0.79) for THR (with 20 predictors) and TKR model (with 24 predictors), respectively. The IECV C-statistics ranged between 0.70-0.74 (THR model) and 0.76-0.82 (TKR model); the IECV calibration slope ranged between 0.93-1.07 (THR model) and 0.92-1.12 (TKR model). Two prediction models with good discrimination and calibration that estimate individuals' risk of THR and TKR have been developed and validated in large-scale, nationally representative data, and are readily automated in electronic patient records

Preliminary Evidence for an Association Between the Composition of the Gut Microbiome and Cognitive Function in Neurologically Healthy Older Adults

Objectives: Dysbiosis of the gut microbiome is implicated in numerous human health conditions. Animal studies have linked microbiome disruption to changes in cognitive functioning, although no study has examined this possibility in neurologically healthy older adults. Methods: Participants were 43 community-dwelling older adults (50-85 years) that completed a brief cognitive test battery and provided stool samples for gut microbiome sequencing. Participants performing ≥ 1 SD below normative performance on two or more tests were compared to persons with one or fewer impaired scores. Results: Mann Whitney U tests revealed different distributions of Bacteroidetes (p = .01), Firmicutes (p = .02), Proteobacteria (p = .04), and Verrucomicrobia (p = .003) between Intact and Impaired groups. These phyla were significantly correlated with cognitive test performances, particularly Verrucomicrobia and attention/executive function measures. Conclusions: The current findings suggest that composition of the gut microbiome is associated with cognitive test performance in neurologically healthy older adults. Future studies are needed to confirm these findings and explore possible mechanisms. (JINS, 2017, 23, 700-705

Identifying mechanisms that predict weight trajectory after bariatric surgery: rationale and design of the biobehavioral trial

Bariatric surgery is currently the most efficacious and durable intervention for severe obesity. The most commonly performed procedures in the United States are the Roux-en-Y gastric bypass and the sleeve gastrectomy, which involve significant anatomic and physiologic alterations that lead to changes in behavior and biology. Unfortunately, many patients experience suboptimal weight loss and/or substantial weight regain. Eating and physical activity/sedentary behaviors, mood, cognition, and the gut microbiome all change postoperatively and have an association with weight change. The longitudinal relationship between changes in the gut microbiome and postoperative weight trajectory has not been explored thoroughly, and the interactive associations among the gut microbiome and the other variables that impact weight have been similarly understudied. The following is a methods and design description for a prospective, 24-month longitudinal study of 144 bariatric surgery patients, at 2 sites, that aimed to identify predictors of weight loss trajectories over 24 months after Roux-en-Y gastric bypass and the sleeve gastrectomy. Specifically, the study will examine the relationships between empirically supported behavioral and biological variables and their combined impact on postoperative weight trajectories. Novel data collection will include intensive measurement of problematic eating behaviors and diet and physical activity postoperatively, which may be altered in parallel with, or in response to, changes observed in the gut microbiota. Identifying postoperative predictors of weight loss and co-morbidity resolution should inform development of novel interventions that are tailored to individual patients’ risk profiles to optimize and sustain more favorable weight trajectories

The science of clinical practice: disease diagnosis or patient prognosis? Evidence about "what is likely to happen" should shape clinical practice.

BACKGROUND: Diagnosis is the traditional basis for decision-making in clinical practice. Evidence is often lacking about future benefits and harms of these decisions for patients diagnosed with and without disease. We propose that a model of clinical practice focused on patient prognosis and predicting the likelihood of future outcomes may be more useful. DISCUSSION: Disease diagnosis can provide crucial information for clinical decisions that influence outcome in serious acute illness. However, the central role of diagnosis in clinical practice is challenged by evidence that it does not always benefit patients and that factors other than disease are important in determining patient outcome. The concept of disease as a dichotomous 'yes' or 'no' is challenged by the frequent use of diagnostic indicators with continuous distributions, such as blood sugar, which are better understood as contributing information about the probability of a patient's future outcome. Moreover, many illnesses, such as chronic fatigue, cannot usefully be labelled from a disease-diagnosis perspective. In such cases, a prognostic model provides an alternative framework for clinical practice that extends beyond disease and diagnosis and incorporates a wide range of information to predict future patient outcomes and to guide decisions to improve them. Such information embraces non-disease factors and genetic and other biomarkers which influence outcome. SUMMARY: Patient prognosis can provide the framework for modern clinical practice to integrate information from the expanding biological, social, and clinical database for more effective and efficient care

Limitations of student-driven formative assessment in a clinical clerkship. A randomised controlled trial

Background Teachers strive to motivate their students to be self-directed learners. One of the methods used is to provide online formative assessment material. The concept of formative assessment and use of these processes is heavily promoted, despite limited evidence as to their efficacy.Methods Fourth year medical students, in their first year of clinical work were divided into four groups. In addition to the usual clinical material, three of the groups were provided with some form of supplementary learning material. For two groups, this was provided as online formative assessment. The amount of time students spent on the supplementary material was measured, their opinion on learning methods was surveyed, and their performance in summative exams at the end of their surgical attachments was measured.Results The performance of students was independent of any educational intervention imposed by this study. Despite its ready availability and promotion, student use of the online formative tools was poor.Conclusion Formative learning is an ideal not necessarily embraced by students. If formative assessment is to work students need to be encouraged to participate, probably by implementing some form of summative assessment.Edward J Palmer and Peter G Devit