Rapid plant trait evolution can alter coastal wetland resilience to sea level rise.

Rapid evolution remains a largely unrecognized factor in models that forecast the fate of ecosystems under scenarios of global change. In this work, we quantified the roles of heritable variation in plant traits and of trait evolution in explaining variability in forecasts of the state of coastal wetland ecosystems. A common garden study of genotypes of the dominant sedge Schoenoplectus americanus, "resurrected" from time-stratified seed banks, revealed that heritable variation and evolution explained key ecosystem attributes such as the allocation and distribution of belowground biomass. Incorporating heritable trait variation and evolution into an ecosystem model altered predictions of carbon accumulation and soil surface accretion (a determinant of marsh resilience to sea level rise), demonstrating the importance of accounting for evolutionary processes when forecasting ecosystem dynamics.

'10% of your medical students will cause 90% of your problems': a prospective correlational study.

OBJECTIVES: Our aim was to explore the relationship between medical student Conscientiousness Index scores and indicators of later clinical performance held in the UK Medical Education Database (UKMED). Objectives were to determine whether conscientiousness in first-year and second-year medical students predicts later performance in medical school and in early practice. Policy implications would permit targeted remediation where necessary or aid in selection. DESIGN: A prospective correlational study. SETTING: A single UK medical school and early years of practice, 2005-2018. PARTICIPANTS: The data were obtained from the UKMED on 858 students. Full outcome data was available for variable numbers of participants, as described in the text. MAIN OUTCOME MEASURES: Scores on the UK Foundation Programme Office's Situational Judgement Test (SJT) and Educational Performance Measure (EPM), the Prescribing Safety Assessment (PSA) and Annual Review of Competency Progression (ARCP) outcomes. RESULTS: Linear regression analysis shows Conscientiousness Index scores significantly correlate with pregraduate and postgraduate performance variables: SJT scores (R=0.373, R2=0.139, B=0.066, p<0.001, n=539); PSA scores (R=0.249, R2=0.062, B=0.343, p<0.001, n=462); EPM decile scores for the first (lowest) decile are significantly lower than the remaining 90% (p=0.003, n=539), as are PSA scores (p<0.001, n=463), and ARCP year 2 scores (p=0.019, n=517). The OR that students in the first decile fail to achieve the optimum ARCP outcome is 1.6126 (CI: 1.1400 to 2.2809, p=0.0069, n=618). CONCLUSIONS: Conscientiousness Index scores in years 1 and 2 of medical school have predictive value for later performance in knowledge, skills and clinical practice. This trait could be used either for selection or for targeted remediation to avoid potential problems in the future.

Do we really need cadavers anymore to learn anatomy in undergraduate medicine?

With the availability of numerous adjuncts or alternatives to learning anatomy other than cadavers (medical imaging, models, body painting, interactive media, virtual reality) and the costs of maintaining cadaver laboratories, it was considered timely to have a mature debate about the need for cadavers in the teaching of undergraduate medicine. This may be particularly pertinent given the exponential growth in medical knowledge in other disciplines, which gives them valid justification for time in already busy medical curricula. In this symposium, the pros and cons of cadaver use in modern medical curricula were debated and audience participation encouraged.

Adjuvant selection regulates gut migration and phenotypic diversity of antigen-specific CD4+ T cells following parenteral immunization.

Infectious diarrheal diseases are the second leading cause of death in children under 5 years, making vaccines against these diseases a high priority. It is known that certain vaccine adjuvants, chiefly bacterial ADP-ribosylating enterotoxins, can induce mucosal antibodies when delivered parenterally. Based on this, we reasoned vaccine-specific mucosal cellular immunity could be induced via parenteral immunization with these adjuvants. Here, we show that, in contrast to the Toll-like receptor-9 agonist CpG, intradermal immunization with non-toxic double-mutant heat-labile toxin (dmLT) from enterotoxigenic Escherichia coli drove endogenous, antigen-specific CD4+ T cells to expand and upregulate the gut-homing integrin α4ß7. This was followed by T-cell migration into gut-draining lymph nodes and both small and large intestines. We also found that dmLT produces a balanced T-helper 1 and 17 (Th1 and Th17) response, whereas T cells from CpG immunized mice were predominantly Th1. Immunization with dmLT preferentially engaged CD103+ dendritic cells (DCs) compared with CpG, and mice deficient in CD103+ DCs were unable to fully license antigen-specific T-cell migration to the intestinal mucosae following parenteral immunization. This work has the potential to redirect the design of existing and next generation vaccines to elicit pathogen-specific immunity in the intestinal tract with non-mucosal immunization.

Relating professionalism and conscientiousness to develop an objective, scalar, proxy measure of professionalism in anaesthetic trainees.

BACKGROUND: The concept of professionalism is complex and subjective and relies on expert judgements. Currently, there are no existing objective measures of professionalism in anaesthesia. However, it is possible that at least some elements of professionalism may be indicated by objective measures. A number of studies have suggested that conscientiousness as a trait is a significant contributor to professionalism. METHODS: A 'Conscientiousness Index' (CI) was developed by collation of routinely collected data from tasks expected to be carried out by anaesthetic trainees such as punctual submission of holiday and 'not-on-call' requests, attendance at audit meetings, timely submission of completed appraisal documentation and sickness/absence notifications. The CI consists of a sum of points deducted from a baseline of 50 for non-completion of these objective and measurable behaviours related to conscientiousness. This was correlated with consultants' formal and informal subjective measures of professionalism in those trainees. Informal, subjective measures of professionalism consisted of a 'Professionalism Index' (PI). The PI consisted of a score developed from consultants' expert, subjective views of professionalism for those trainees. Formal, subjective measures of professionalism consisted of a score derived from comments made by consultants in College Tutor feedback forms on their views on the professionalism of those trainees (College Tutor feedback; CT). The PI and CT scores were correlated against the CI using a Pearson or Spearman correlation coefficient. RESULTS: There was a negative, but not statistically significant, relationship between the CI and formal, subjective measures of professionalism; CT scores (r = -0.341, p = 0.06), but no correlation between CI and consultants informal views of trainees' professionalism; the PI scores (r s = -0.059, p = 0.759). CONCLUSIONS: This may be due the 'failure to fail' phenomenon due to the high stakes nature of raising concerns of professionalism in postgraduate healthcare professionals or may be that the precision of the tool may be insufficient to distinguish between trainees who generally show highly professional behaviour. Future development of the tool may need to include more of the sub-facets of conscientiousness. Independently of a relationship with the construct of professionalism, a measure of conscientiousness might be of interest to future employers.

The Impact of Systemic Therapy Beyond First-line Treatment for Advanced Cervical Cancer.

AIMS: Despite recent advances in the primary and secondary prevention of cervical cancer, a significant number of women present with or develop metastatic disease. There is currently no consensus on the standard of care for second-line systemic treatment of recurrent/metastatic cervical cancer. The purpose of this study was to evaluate the second-line systemic therapy used and the associated outcomes in a single cancer centre. MATERIALS AND METHODS: A retrospective review of patients with cervical cancer who received one or more lines of treatment for recurrent or metastatic cervical cancer at the Royal Marsden Hospital between 2004 and 2014 was carried out. The primary objective was to establish the types of second-line systemic treatment used. Secondary end points included objective response rate, progression-free survival and overall survival after second-line therapy. RESULTS: In total, 75 patients were included in the study; 53 patients (70.7%) received second-line therapy for recurrent/metastatic disease. The most common second-line therapy was weekly paclitaxel (28.3%). Carboplatin-based chemotherapy (24.5%), targeted agent monotherapy within clinical trials (22.6%), docetaxel-based chemotherapy (13.2%), topotecan (9.4%) and gemcitabine (1.9%) were also used. The objective response rate to second-line therapy was 13.2%, which included three partial responses to carboplatin and paclitaxel, two partial responses to docetaxel-based chemotherapy, one partial response to weekly paclitaxel and one partial response to cediranib. Twenty-two patients (41.5%) achieved stable disease at 4 months. The median progression-free survival for women treated with second-line therapy was 3.2 months (95% confidence interval 2.1-4.3) and median overall survival was 9.3 months (95% confidence interval 6.4-12.5). Thirty-nine per cent of patients received third-line therapy. CONCLUSION: Seventy per cent of patients treated with first-line systemic therapy for recurrent/metastatic cervical cancer subsequently received second-line treatment but response rates were poor. There remains no standard of care for second-line systemic therapy for advanced cervical cancer. Patients should be considered for clinical trials whenever feasible, including novel targeted agents and immunotherapy.

Environmental signaling: from environmental estrogens to endocrine-disrupting chemicals and beyond.

The landmark report (Herbst et al. 1971) linking prenatal treatment with a synthetic estrogen, diethylstilbestrol (DES), to cancer at puberty in women whose mothers took the drug while pregnant ushered in an era of research on delayed effects of such exposures on functional outcomes in offspring. An animal model developed in our laboratory at the National Institute of Environmental Health Sciences confirmed that DES was the carcinogen and exposure to DES caused, as well, functional alterations in the reproductive, endocrine, and immune systems of male and female mice treated in utero. DES was also being used in agriculture and we discovered, at the first meeting on Estrogens in the Environment in 1979 (Estrogens in the Environment, 1980), that many environmental contaminants were also estrogenic. Many laboratories sought to discern the basis for estrogenicity in environmental chemicals and to discover other hormonally active xenobiotics. Our laboratory elucidated how DES and other estrogenic compounds worked by altering differentiation through epigenetic gene imprinting, helping explain the transgenerational effects found in mice and humans. At the Wingspread Conference on the Human-Wildlife Connection in 1991 (Advances in Modern Environmental Toxicology, 1992), we learned that environmental disruption of the endocrine system occurred in many species and phyla, and the term endocrine disruption was introduced. Further findings of transgenerational effects of environmental agents that mimicked or blocked various reproductive hormones and the ubiquity of environmental signals, such as bisphenol A increased concern for human and ecological health. Scientists began to look at other endocrine system aspects, such as cardiovascular and immune function, and other nuclear receptors, with important observations regarding obesity and metabolism. Laboratories, such as ours, are now using stem cells to try to understand the mechanisms by which various environmental signals alter cell differentiation. Since 2010, research has shown that trauma and other behavioral inputs can function as 'environmental signals,' can be encoded in gene regulation networks in a variety of cells and organs, and can be passed on to subsequent generations. So now we come full circle: environmental chemicals mimic hormones or other metabolic signaling molecules and now behavioral experience can be transduced into chemical signals that also modify gene expression.

Mediators of inflammation and regeneration.

Characterization of the molecular response under caries lesions requires a robust and reliable transcript isolation system, and analysis of data indicated that collection of extracted teeth in either liquid nitrogen/RNA-stabilizing solution facilitated this. Subsequent transcriptional analysis indicated higher general activity in carious pulps, while characterization of inflammatory mediators, including cytokines and S100 proteins, highlighted increasing expression levels associated with both microbial front progression and elevated cellular immune response. Analysis of the pleiotropic hormone adrenomedullin (ADM) indicated that transcript and protein levels are increased in pulpal tissue during caries, and that protein levels sequestered in dentin due to primary dentinogenesis are comparable with those of TGF-ß1. Expression analysis of a leucine-rich-repeat-containing protein (LRRC15/Lib) indicated that this highly conserved molecule was up-regulated during caries, is transcriptionally regulated by pro-inflammatory stimuli, and is relatively abundant in mineralized tissues.

Toxicity associated with capecitabine plus oxaliplatin in colorectal cancer before and after an institutional policy of capecitabine dose reduction.

BACKGROUND: Capecitabine plus oxaliplatin (CAPOX) is an established treatment option in colorectal cancer, but can be associated with severe toxicities. METHODS: Following reporting of severe diarrhoea and dehydration with capecitabine 2000 mg m(-2) per day plus oxaliplatin every 3 weeks (CAPOX 2000) in 2006, we instituted a policy change to reduce capecitabine dose to 1700 mg m(-2) per day (CAPOX 1700). We undertook a retrospective analysis comparing toxicities encountered before and after this dose change. RESULTS: Of the 400 patients treated, no significant differences were seen between the CAPOX 2000 and CAPOX 1700 in grades 3 and 4 diarrhoea (21% vs 19%; P=0.80), stomatitis (0% vs 1%; P=0.50) or grades 2-4 hand foot syndrome (16% vs 11%; P=0.18). Grades 3 and 4 neutropenia (9.5% vs 3.5%; P=0.03) and all grades hyperbilirubinaemia (60% vs 40%; P<0.0001) were significantly reduced with CAPOX 1700. Rates of hospitalisation due to toxicities were not different between two groups (13% vs 11%; P=0.53). CONCLUSIONS: No clinically or statistically significant differences in gastrointestinal toxicities or hospitalisation rate were seen after reducing our routine capecitabine dose from CAPOX 2000 to CAPOX 1700.

Student attitudes to peer physical examination: a qualitative study of changes in expressed willingness to participate.

BACKGROUND: A number of studies have explored student attitudes to examining each other (peer physical examination: PPE). Differences have emerged in whether students prefer to be examined by friends or strangers. Changes have been reported in how students feel about PPE if asked before or after the PPE programme commences. RESEARCH INTENTION: Since a Grounded Theory paradigm was employed, there was no formal research hypothesis: the research intention was to explore factors which might underlie changes in student willingness to undertake PPE following familiarity with the process. METHODS: Students who had completed an Examining Fellow Students Questionnaire at the beginning and end of the academic year, and who had indicated a change in willingness to participate, were invited to attend focus groups. Four focus groups were convened and transcripts were analysed for common themes. RESULTS: Surprisingly, students downplayed the significance of changes. Also unexpectedly, dichotomous views emerged on familiarity, with some students preferring friends for examination and others preferring strangers. Staff embarrassment also emerged as a factor inhibiting student participation. CONCLUSIONS: The significance of reported changes in attitudes to PPE may have been exaggerated. Proposals for increasing the willingness of students to participate in PPE are developed from the emergent themes.

Cardio-selective and non-selective beta-blockers in chronic obstructive pulmonary disease: effects on bronchodilator response and exercise.

BACKGROUND: Patients with chronic obstructive pulmonary disease (COPD) often have co-existing cardiovascular disease and may require beta-blocker treatment. There are limited data on the effects of beta-blockers on the response to inhaled beta2-agonists and exercise capacity in patients with COPD. OBJECTIVE: To determine the effects of different doses of cardio-selective and non-selective beta-blockers on the acute bronchodilator response to beta-agonists in COPD, and to assess their effects on exercise capacity. METHODS: A double-blind, randomized, three-way cross-over (metoprolol 95 mg, propranolol 80 mg, placebo) study with a final open-label high-dose arm (metoprolol 190 mg). After 1 week of each treatment, the bronchodilator response to salbutamol was measured after first inducing bronchoconstriction using methacholine. Exercise capacity was assessed using the incremental shuttle walk test. RESULTS: Eleven patients with moderate COPD were recruited. Treatments were well-tolerated although two did not participate in the high-dose metoprolol phase. The area under the salbutamol-response curve was lower after propranolol compared with placebo (P=0.0006). The area under the curve also tended to be lower after high-dose metoprolol (P=0.076). The per cent recovery of the methacholine-induced fall was also lower after high-dose metoprolol (P=0.0018). Low-dose metoprolol did not alter the bronchodilator response. Oxygen saturation at peak exercise was lower with all beta-blocker treatments (P=0.046). CONCLUSION: Non-selective beta-blockers and high doses of cardio-selective beta-blockers may inhibit the bronchodilator response to beta2-agonists in patients with COPD. Beta-blockers were also associated with lower oxygen saturation during exercise. The clinical significance of these adverse effects is uncertain in view of the benefits of beta-blocker treatment for cardiovascular disease.

Audit of acute admissions of chronic obstructive pulmonary disease: inpatient management and outcome.

BACKGROUND: Despite the publication of several management guidelines for exacerbations of chronic obstructive pulmonary disease (COPD), there is little information on standards of care in clinical practice. The aim of this audit was to examine the assessment, management and outcome of COPD admissions to a secondary and tertiary referring New Zealand hospital during two different seasons. Compliance to current recommendations was examined and compared with the available international published work. METHODS: All COPD-related admissions to Waikato Hospital during the months of May and October 2004 were reviewed. Ninety-four cases (from 84 patients) were audited. RESULTS: General characteristics, clinical features and lung function tests were similar to that of other cohorts. Twenty-three per cent of the admissions were Maori and the mean age of Maori admissions were significantly less than that of the non-Maori admissions (57 and 72 years, respectively; P = 0.0001). The geometric mean length of stay was 3.4 days, which is significantly less than most other reported hospital lengths of stays related to exacerbations of COPD. Fifty-five per cent of the cohort was admitted more than once to the hospital for COPD in the 12 months before the index admission. Thirteen per cent of all admissions received assisted ventilation. Overall 30-day mortality was 8% and the 12-month mortality was 31%. Decreased body mass index was a risk factor for death as was an increased CURB-65 (confusion, urea, respiratory rate, blood pressure age) score--a simple bedside assessment score, which has previously been used to predict mortality in patients with community-acquired pneumonia. CONCLUSION: This audit documented the general characteristics, assessment, management and outcome of the COPD admissions to a secondary New Zealand hospital. Further investigations into factors contributing to shorter length of stay and predictors of mortality are needed.

Evaluating a poetry workshop in medical education.

This study aimed at evaluating how doing poetry could affect students' understanding of medical practice and at assessing the effectiveness of the evaluation method used. Qualitative research was carried out on the experiences of medical students participating in a poetry workshop, followed by some quantitative analysis. The study was conducted at Peninsula Medical School and St Ives, Cornwall, UK, with three medical students, a poet and a pathologist as participants. Data were collected by interviews, observation and web access. "Doing poetry" with a professional poet was found to assist communication between doctors and patients as it enhanced skills of observation, heightened awareness of the effect of language and fostered deep reflection. Poetry was also found to offer an outlet for medics and patients. The voluntary workshop attracted three participants; however, it might have had an effect on the wider student community because the poetry website received 493 hits in four months. Qualitative methods worked well as a tool for evaluation. "Doing poetry for poetry's sake" seemed to foster the development of skills related to empathy. The opportunity to do poetry should be made available to medical students as part of a wider arts and humanities programme.

The Scottish doctor--learning outcomes for the medical undergraduate in Scotland: a foundation for competent and reflective practitioners.

This paper describes a set of learning outcomes that clearly define the abilities of medical graduates from any of the five Scottish medical schools. The outcomes are divided into 12 domains that fit into one of three essential elements for the competent and reflective medical practitioner.

Oestrogen-mediated suppression of tumour necrosis factor alpha-induced apoptosis in MCF-7 cells: subversion of Bcl-2 by anti-oestrogens.

In oestrogen receptor (ER)-positive breast carcinoma cells, 17beta-oestradiol suppresses a dose-dependent induction of cell death by tumour necrosis factor alpha (TNF). The ability of oestrogens to promote cell survival in ER-positive breast carcinoma cells is linked to a coordinate increase in Bcl-2 expression, an effect that is blocked with the pure anti-oestrogen ICI 182,780. The role of Bcl-2 in MCF-7 cell survival was confirmed by stable overexpression of Bcl-2 which resulted in suppression of apoptosis induced by doxorubicin (DOX), paclitaxel (TAX) and TNF as compared to vector-control cells. The pure anti-oestrogen ICI 182,780 in combination with TNF, DOX or TAX potentiated apoptosis in vector-transfected cells. Interestingly, pre-treatment with ICI 182,780 markedly enhanced chemotherapeutic drug- or TNF-induced apoptosis in Bcl-2 expressing cells, an effect that was correlated with ICI 182,780 induced activation of c-Jun N-terminal kinase. Our results suggest that the effects of oestrogens/anti-oestrogens on the regulation of apoptosis may involve coordinate activation of signalling events and Bcl-2 expression.

Promoter CpG methylation of Hox-a10 and Hox-a11 in mouse uterus not altered upon neonatal diethylstilbestrol exposure.

Mouse abdominal B-like Hoxa genes are expressed and functionally required in the developing reproductive tracts. Mice lacking either Hoxa-10 or Hoxa-11, two of the AbdB Hoxa genes, exhibit abnormal uterine development similar to that induced by in utero diethylstilbestrol (DES) exposure. Indeed, uterine Hoxa-10 and Hoxa-11 expression is potently repressed by perinatal DES exposure, providing a potential molecular mechanism for DES-induced reproductive tract malformations. We have shown previously that DES can permanently alter uterine lactoferrin gene expression through modulation of the lactoferrin promoter methylation pattern. Here we ask whether a similar mechanism also functions to deregulate uterine Hoxa-10 or Hoxa-11 expression during neonatal DES exposure. We mapped the Hoxa-10 promoter by cloning a 1.485 kb DNA fragment 5' of the Hoxa-10 exon1a. A 5' rapid amplification of cDNA ends (RACE) experiment revealed a transcription start site for the a10-1 transcript. Functional analysis of the proximal 200-bp sequences demonstrated significant promoter activity, confirming the location of the Hoxa-10 promoter. Moreover, methylation assays performed on eight CpGs in Hoxa-10 and 19 CpGs in Hoxa-11 proximal promoters demonstrated that all these CpGs were highly unmethylated in both control and DES-dosed mice from postnatal day 5 to day 30. Significant methylation around Hoxa-10 and Hoxa-11 promoters was only observed in DES-induced uterine carcinomas in 18-mo-old mice. Our results suggest that DES-induced downregulations of Hoxa-10 or Hoxa-11 gene expression are not associated with methylation changes in their proximal promoters and that gene imprinting by developmental DES exposure may be a gene-specific phenomenon.

Endocrine disruption in sexual differentiation and puberty. What do pseudohermaphroditic polar bears have to do with the practice of pediatrics?

What do pseudohermaphroditic polar bears and girls with premature breast development have in common? Hormones. Sexual differentiation and the initiation of secondary sexual characteristics, such as breast growth, are both under the control of the sex hormones estrogen and androgen. Abnormal differentiation of the internal or external genitalia in bears and early onset of breast development in girls also may have a common element--exposure to environmental hormones.

Green fluorescent protein (GFP) as a marker of aryl hydrocarbon receptor (AhR) function in developing zebrafish (Danio rerio).

We developed an inducible in vivo reporter system to examine expression of the aryl hydrocarbon receptor (AhR) during development in zebrafish (Danio rerio). AhR is a ligand-activated transcription factor that mediates the toxic actions of environmental contaminants such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Induction of cytochrome P4501A1 (CYP1A1) is an early biomarker of AhR activation. A 1905 base pair region of the human CYP1A1 promoter/enhancer region was regulated by AhR in zebrafish liver cells after exposure to TCDD (10 nM) in a transient transfection assay. This regulatory region was fused to the cDNA sequence encoding green fluorescent protein (GFP) of jellyfish (Aequorea victoria). Transgenic zebrafish were generated to express this AhR-regulated GFP construct. Injected fish exposed to TCDD exhibited induction of GFP in the eye, nose, and vertebrae of zebrafish embryos (48 and 72 hr after fertilization) compared to vehicle controls (DMSO), which did not express GFP. To investigate whether AhR-regulated GFP expression correlated with sites of TCDD toxicity, we exposed wild-type zebrafish to DMSO or TCDD and examined them for morphologic abnormalities. By 5 days after fertilization, TCDD-exposed fish exhibited gross dysmorphogenesis in cranio-facial and vertebral development.