Structure of an Aspergillus fumigatus old yellow enzyme (EasA) involved in ergot alkaloid biosynthesis

This is the published version.The Aspergillus fumigatus old yellow enzyme (OYE) EasA reduces chanoclavine-I aldehyde to dihydrochanoclavine aldehyde and works in conjunction with festuclavine synthase at the branchpoint for ergot alkaloid pathways. The crystal structure of the FMN-loaded EasA was determined to 1.8 Å resolution. The active-site amino acids of OYE are conserved, supporting a similar mechanism for reduction of the α/β-unsaturated aldehyde. The C-terminal tail of one monomer packs into the active site of a monomer in the next asymmetric unit, which is most likely to be a crystallization artifact and not a mechanism of self-regulation

Maternal infection and risk of intrapartum death: a population based observational study in South Asia.

BACKGROUND: Approximately 1.2 million stillbirths occur in the intrapartum period, and a further 717,000 annual neonatal deaths are caused by intrapartum events, most of which occur in resource poor settings. We aim to test the 'double-hit' hypothesis that maternal infection in the perinatal period predisposes to neurodevelopmental sequelae from an intrapartum asphyxia insult, increasing the likelihood of an early neonatal death compared with asphyxia alone. This is an observational study of singleton newborn infants with signs of intrapartum asphyxia that uses data from three previously conducted cluster randomized controlled trials taking place in rural Bangladesh and India. METHODS: From a population of 81,778 births in 54 community clusters in rural Bangladesh and India, we applied mixed effects logistic regression to data on 3890 singleton infants who had signs of intrapartum asphyxia, of whom 769 (20%) died in the early neonatal period. Poor infant condition at five minutes post-delivery was our proxy measure of intrapartum asphyxia. We had data for two markers of maternal infection: fever up to three days prior to labour, and prolonged rupture of membranes (PROM). Cause-specific verbal autopsy data were used to validate our findings using previously mentioned mixed effect logistic regression methods and the outcome of a neonatal death due to intrapartum asphyxia. RESULTS: Signs of maternal infection as indicated by PROM, combined with intrapartum asphyxia, increased the risk of an early neonatal death relative to intrapartum asphyxia alone (adjusted odds ratio (AOR) 1.28, 95% CI 1.03 - 1.59). Results from cause-specific verbal autopsy data verified our findings where there was a significantly increased odds of a early neonatal death due to intrapartum asphyxia in newborns exposed to both PROM and intrapartum asphyxia (AOR: 1.52, 95% CI 1.15 - 2.02). CONCLUSIONS: Our data support the double-hit hypothesis for signs of maternal infection as indicated by PROM. Interventions for pregnant women with signs of infection, to prevent early neonatal deaths and disability due to asphyxia, should be investigated further in resource-poor populations where the chances of maternal infection are high

Racial/ethnic and socioeconomic survival disparities for children and adolescents with central nervous system tumours in the United States, 2000-2015.

BACKGROUND AND OBJECTIVES: Central nervous system (CNS) malignancy is the commonest cause of cancer death in children and adolescents (0-19 years) in high-income settings. There is limited data on survival inequalities by race/ethnicity and socioeconomic position (SEP), for young patients, we aim to analyse their influence on survival from childhood CNS tumour. METHODS: 9577 children and adolescents diagnosed with primary malignant CNS tumours during 2000-2015, followed up until Dec 31 st, 2015, and reported to cancer registries (Surveillance, Epidemiology and End Results programme) were included in the analysis. Cox regression models estimated the hazard ratios for race/ethnicity, SEP, and individual insurance status, adjusting for sex, age, diagnostic period, and tumour type. Individual-level insurance status data were available from 2007. RESULTS: 62.5 % children and adolescents were non-Hispanic White, 10.6 % were non-Hispanic Black and 26.9 % were Hispanic. Race/ethnicity was strongly associated with survival (p < 0.001), even after adjusting for SEP, with Black (HR = 1.39 [95 %CI 1.23-1.58]) and Hispanic children (HR = 1.40 [95 %CI 1.28-1.54]) having higher hazards of death than White children. This association remained after adjusting for insurance status. There was an apparent positive association between SEP and survival that was largely attenuated after adjustment for insurance status (p = 0.20). Survival was comparable between those privately and Medicaid-insured. CONCLUSIONS: Non-Hispanic Black and Hispanic children had lower survival than their White counterparts. This association, not fully explained by differences in SEP, tumour subtype or health insurance, could be related to racially/ethnically-driven barriers to optimal healthcare, warranting further investigation

Future Supply of Medical Radioisotopes for the UK Report 2014

The UK has no research nuclear reactors and relies on the importation of 99Mo and other medical radioisotopes (e.g. Iodine-131) from overseas (excluding PET radioisotopes). The UK is therefore vulnerable not only to global shortages, but to problems with shipping and importation of the products. In this context Professor Erika Denton UK national Clinical Director for Diagnostics requested that the British Nuclear Medicine Society lead a working group with stakeholders including representatives from the Science & Technology Facilities Council (STFC) to prepare a report. The group had a first meeting on 10 April 2013 followed by a working group meeting with presentations on 9th September 2013 where the scope of the work required to produce a report was agreed. The objectives of the report are: to describe the status of the use of medical radioisotopes in the UK; to anticipate the potential impact of shortages for the UK; to assess potential alternative avenues of medical radioisotope production for the UK market; and to explore ways of mitigating the impact of medical radioisotopes on patient care pathways. The report incorporates details of a visit to the Cyclotron Facilities at Edmonton, Alberta and at TRIUMF, Vancouver BC in Canada by members of the report team.Comment: 121 page

Effect of scaling up women's groups on birth outcomes in three rural districts in Bangladesh: a cluster-randomised controlled trial

SummaryBackgroundTwo recent trials have shown that women's groups can reduce neonatal mortality in poor communities. We assessed the effectiveness of a scaled-up development programme with women's groups to address maternal and neonatal care in three rural districts of Bangladesh.Methods18 clusters (with a mean population of 27 953 [SD 5953]) in three districts were randomly assigned to either intervention or control (nine clusters each) by use of stratified randomisation. For each district, cluster names were written on pieces of paper, which were folded and placed in a bottle. The first three cluster names drawn from the bottle were allocated to the intervention group and the remaining three to control. All clusters received health services strengthening and basic training of traditional birth attendants. In intervention clusters, a facilitator convened 18 groups every month to support participatory action and learning for women, and to develop and implement strategies to address maternal and neonatal health problems. Women were eligible to participate if they were aged 15–49 years, residing in the project area, and had given birth during the study period (Feb 1, 2005, to Dec 31, 2007). Neither study investigators nor participants were masked to treatment assignment. In a population of 229 195 people (intervention clusters only), 162 women's groups provided coverage of one group per 1414 population. The primary outcome was neonatal mortality rate (NMR). Analysis was by intention to treat. This trial is registered as an International Standard Randomised Controlled Trial, number ISRCTN54792066.FindingsWe monitored outcomes for 36 113 births (intervention clusters, n=17 514; control clusters, n=18 599) in a population of 503 163 over 3 years. From 2005 to 2007, there were 570 neonatal deaths in the intervention clusters and 656 in the control clusters. Cluster-level mean NMR (adjusted for stratification and clustering) was 33·9 deaths per 1000 livebirths in the intervention clusters compared with 36·5 per 1000 in the control clusters (risk ratio 0·93, 95% CI 0·80–1·09).InterpretationFor participatory women's groups to have a significant effect on neonatal mortality in rural Bangladesh, detailed attention to programme design and contextual factors, enhanced population coverage, and increased enrolment of newly pregnant women might be needed.FundingWomen and Children First, the UK Big Lottery Fund, Saving Newborn Lives, and the UK Department for International Development

A three gene DNA methylation biomarker accurately classifies early stage prostate cancer

Background: We identify and validate accurate diagnostic biomarkers for prostate cancer through a systematic evaluation of DNA methylation alterations. Materials and methods: We assembled three early prostate cancer cohorts (total patients = 699) from which we collected and processed over 1300 prostatectomy tissue samples for DNA extraction. Using real-time methylation-specific PCR, we measured normalized methylation levels at 15 frequently methylated loci. After partitioning sample sets into independent training and validation cohorts, classifiers were developed using logistic regression, analyzed, and validated. Results: In the training dataset, DNA methylation levels at 7 of 15 genomic loci (glutathione S-transferase Pi 1 [GSTP1], CCDC181, hyaluronan, and proteoglycan link protein 3 [HAPLN3], GSTM2, growth arrest-specific 6 [GAS6], RASSF1, and APC) showed large differences between cancer and benign samples. The best binary classifier was the GAS6/GSTP1/HAPLN3 logistic regression model, with an area under these curves of 0.97, which showed a sensitivity of 94%, and a specificity of 93% after external validation. Conclusion: We created and validated a multigene model for the classification of benign and malignant prostate tissue. With false positive and negative rates below 7%, this three-gene biomarker represents a promising basis for more accurate prostate cancer diagnosis

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

Subjective Cognitive Decline in Older Adults: An Overview of Self-Report Measures Used Across 19 International Research Studies

Research increasingly suggests that subjective cognitive decline (SCD) in older adults, in the absence of objective cognitive dysfunction or depression, may be a harbinger of non-normative cognitive decline and eventual progression to dementia. Little is known, however, about the key features of self-report measures currently used to assess SCD. The Subjective Cognitive Decline Initiative (SCD-I) Working Group is an international consortium established to develop a conceptual framework and research criteria for SCD (Jessen et al., 2014, Alzheimers Dement 10, 844-852). In the current study we systematically compared cognitive self-report items used by 19 SCD-I Working Group studies, representing 8 countries and 5 languages. We identified 34 self-report measures comprising 640 cognitive self-report items. There was little overlap among measures- approximately 75% of measures were used by only one study. Wide variation existed in response options and item content. Items pertaining to the memory domain predominated, accounting for about 60% of items surveyed, followed by executive function and attention, with 16% and 11% of the items, respectively. Items relating to memory for the names of people and the placement of common objects were represented on the greatest percentage of measures (56% each). Working group members reported that instrument selection decisions were often based on practical considerations beyond the study of SCD specifically, such as availability and brevity of measures. Results document the heterogeneity of approaches across studies to the emerging construct of SCD. We offer preliminary recommendations for instrument selection and future research directions including identifying items and measure formats associated with important clinical outcome

Thyroid Hormone Therapy for Older Adults with Subclinical Hypothyroidism.

BACKGROUND: The use of levothyroxine to treat subclinical hypothyroidism is controversial. We aimed to determine whether levothyroxine provided clinical benefits in older persons with this condition. METHODS: We conducted a double-blind, randomized, placebo-controlled, parallel-group trial involving 737 adults who were at least 65 years of age and who had persisting subclinical hypothyroidism (thyrotropin level, 4.60 to 19.99 mIU per liter; free thyroxine level within the reference range). A total of 368 patients were assigned to receive levothyroxine (at a starting dose of 50 μg daily, or 25 μg if the body weight was <50 kg or the patient had coronary heart disease), with dose adjustment according to the thyrotropin level; 369 patients were assigned to receive placebo with mock dose adjustment. The two primary outcomes were the change in the Hypothyroid Symptoms score and Tiredness score on a thyroid-related quality-of-life questionnaire at 1 year (range of each scale is 0 to 100, with higher scores indicating more symptoms or tiredness, respectively; minimum clinically important difference, 9 points). RESULTS: The mean age of the patients was 74.4 years, and 396 patients (53.7%) were women. The mean (±SD) thyrotropin level was 6.40±2.01 mIU per liter at baseline; at 1 year, this level had decreased to 5.48 mIU per liter in the placebo group, as compared with 3.63 mIU per liter in the levothyroxine group (P<0.001), at a median dose of 50 μg. We found no differences in the mean change at 1 year in the Hypothyroid Symptoms score (0.2±15.3 in the placebo group and 0.2±14.4 in the levothyroxine group; between-group difference, 0.0; 95% confidence interval [CI], -2.0 to 2.1) or the Tiredness score (3.2±17.7 and 3.8±18.4, respectively; between-group difference, 0.4; 95% CI, -2.1 to 2.9). No beneficial effects of levothyroxine were seen on secondary-outcome measures. There was no significant excess of serious adverse events prespecified as being of special interest. CONCLUSIONS: Levothyroxine provided no apparent benefits in older persons with subclinical hypothyroidism. (Funded by European Union FP7 and others; TRUST ClinicalTrials.gov number, NCT01660126 .)

Thrive: Success Strategies for the Modern-Day Faculty Member

The THRIVE collection is intended to help faculty thrive in their roles as educators, scholars, researchers, and clinicians. Each section contains a variety of thought-provoking topics that are designed to be easily digested, guide personal reflection, and put into action. Please use the THRIVE collection to help: Individuals study topics on their own, whenever and wherever they want Peer-mentoring or other learning communities study topics in small groups Leaders and planners strategically insert faculty development into existing meetings Faculty identify campus experts for additional learning, grand rounds, etc. If you have questions or want additional information on a topic, simply contact the article author or email [email protected]://digitalcommons.unmc.edu/facdev_books/1000/thumbnail.jp