bluuebunny/crossref_metadata_2025 huggingface dataset:
Evaluation of an Ophthalmology Session for Third-Year Medical Students at the University of Colorado School of Medicine
Authors: Kelley Judas , Singh Jasleen
Published: February 2018

Background Medical school ophthalmology education continues to be marginalized, creating the challenge of teaching students how to adequately diagnose and manage common ocular diseases in a limited time.

Objective This study aimed to improve the ophthalmic medical knowledge and clinical skills of third-year medical students.

Methods This curriculum was provided to 76 out of 124 third-year medical students in the 2016 class at the University of Colorado-Denver School of Medicine program. It was a half-day session that incorporated lectures, problem-based cases, and clinical skills. Participating students were given a self-reflection survey on their knowledge at the beginning and end of the session. Participating students were given a pre-test and post-test 6 months later via SurveyMonkey. Another quiz was given to all students within the class. Comparisons of pre- and post-tests, pre- and post-surveys, and quiz results in the participating and nonparticipating groups were made.

Results Participating students' mean pre-test score was 61.8% (n = 76) and post-test score was 72.3% (n = 47), p < 0.01, indicating a significant increase in knowledge. There was an increase in 2 points on the Likert scale of understanding in ophthalmology between surveys. Participating students received a quiz mean score of 61.2%, which was significantly higher than those in the nonparticipating group (54.3%), p < 0.05.

Conclusion This session improved medical students' confidence and medical knowledge in ophthalmology.
Towards a manifesto for a critical digital humanities: critiquing the extractive capitalism of digital society
Authors: Grimshaw Mike
Published: February 2018

This article proceeds in two distinct parts. The first section engages with a deliberately small number of popular texts written by discriminating and interrogative consumers and producers of digital culture and society. While these may be dismissed as journalistic texts and sources by those of a more focused academic intent, here these texts are used because they are the connection between academic engagement and wider public readership. As such, they frame what can be termed the critical public engagement with digital capitalism. These texts are read in tandem with my thesis of immaterial capitalism and Marazzi’s’ The Violence of Financial Capitalism. The paper then concludes with what can be described as the ‘manifesto turn’ by raising some questions for a renewed engagement with digital society, to be undertaken from what is termed, an emergent critical digital humanities, as the site of critique and resistance. This is an exercise in what can be labelled Mongrel methodology and ideology, a neo-logism deliberately provocative in intent to signal a post-academic approach, chosen over such traditional descriptors as mixed-methods or assemblage and the like. As such, it may draw on Marxist thought but is not Marxist in ideology or final intent; it is critical of capitalism but acknowledges our on-going existence and possibilities within it; it is written by an academic seeking to act as intermediary between academic and non-academic readings and responses. It is a deliberate act of provocation as a manifesto call for change.
Promoting Addiction Medicine Teaching through Functional Mentoring by Co-Training Generalist Chief Residents with Faculty Mentors
Authors: Alford Daniel P. , Carney Brittany L. , Jackson Angela H. , Brett Belle , Bridden Carly , Winter Michael , Samet Jeffrey H.
Published: February 2018

Background: Generalist physicians should play a vital role in identifying and managing individuals with substance use but are inadequately trained to do so. Methods: This 5-year (2008–2012) controlled educational study assessed whether internal medicine and family medicine chief residents’ (CRs) addiction medicine teaching increased by co-training with faculty mentors at a Chief Resident Immersion Training (CRIT) program in addiction medicine. All CRIT CR attendees identified a residency program faculty mentor to support addiction medicine teaching after CRIT through functional mentoring with a focus on developing and implementing an Addiction Medicine Teaching Project (“Teaching Project”). Approximately half of the CRs attended CRIT with their mentor ( co-trained) and half without their mentor ( solo-trained). Addiction medicine teaching outcomes were compared between groups using 6- and 11-month questionnaires and 4 bimonthly teaching logs. Of co-trained CRs, mentor characteristics that positively influenced addiction medicine teaching outcomes were identified. Results: One hundred CRs from 74 residency programs attended CRIT from 2008 to 2012; 47 co-trained with their mentors and 53 solo-trained without their mentors. At 6-month follow-up, the co-trained CRs were more likely to meet at least monthly with their mentor (22.7% vs. 9.6%, P < .01) and more likely to identify their mentor as a facilitator for Teaching Project implementation (82.2% vs. 38.5%, P < .01). At 11-month follow-up, a higher percentage of co-trained CRs had completed their Teaching Project (34.0% vs. 15.1%, P < .05). Both CR groups had similarly large increases in other addiction medicine teaching outcomes. Mentors with more experience, including years of teaching, was associated with better CR Teaching Project outcomes. Conclusions: Co-training generalist chief residents with a faculty mentor appeared to facilitate functional mentoring–driven Teaching Project implementation but did not further increase already high levels of other addiction medicine teaching. Faculty mentors with more years of teaching experience were more effective in facilitating Teaching Project implementation.
Past-Year Nonmedical use of Prescription Drugs among Women on Probation and Parole: A Cross-Sectional Study
Authors: Hall Martin T. , Ball Diana , Sears Jeanelle , Higgins George E. , Logan T K , Golder Seana
Published: February 2018

Background: Prescription drug–related overdose deaths have increased dramatically in recent years. Women in the justice system experience high rates of drug use, victimization, trauma symptoms, and other health problems and would appear to be at high risk for nonmedical use of prescription drugs (NMUPD). This study will be among the first to describe prevalence and correlates of NMUPD among this population. Methods: This cross-sectional study collected data from 406 victimized women on probation and parole between 2010 and 2012. In a multiple logistic regression model, we differentiated women who reported past-year NMUPD from those who did not using demographic, health, other drug use, substance use treatment, and trauma symptom severity variables. Results: Past-year NMUPD was reported by 26.8% ( n = 109) of the overall sample. Women reporting NMUPD were significantly younger and more likely to be white. Past-year use of alcohol (adjusted odds ratio [AOR]: 3.3; 95% confidence interval [CI]: 1.8–6.1), marijuana (AOR: 3.6; 95% CI: 1.8–7.0), methamphetamines (AOR: 6.1; 95% CI: 1.7–21.3), and heroin (AOR: 8.4; 95% CI: 2.0–35.2) were significantly associated with NMUPD. Additionally, each unit increase in the measure assessing bodily pain was associated with a 40% increase (AOR: 1.4; 95% CI: 1.1–1.7) in the odds of NMUPD. Finally, meeting diagnostic criteria for posttraumatic stress disorder almost doubled (AOR: 1.9; 95% CI: 1.1–3.4) the odds of reporting past-year NMUPD. Conclusions: Victimized women on probation and parole report high rates of NMUPD, and this behavior intersects with other complex social, behavioral, psychological, and physical needs. The authors recommend increased access to trauma-informed correctional care among women in the justice system.
Alcohol and Drug use among Deaf and Hard-of-Hearing Individuals: A Secondary Analysis of NHANES 2013–2014
Authors: Anderson Melissa L. , Chang Bei-Hung , Kini Nisha
Published: February 2018

Background: Within the field of behavioral health research, one of the most understudied populations is the US deaf and hard-of-hearing (D/HH) population—a diverse group of individuals with hearing loss that have varied language and communication preferences, community affiliations, and sociocultural norms. Recent research identified concerning behavioral health disparities experienced by the D/HH population; yet, little research has been conducted to extend these findings to the topic of substance use disorder. Methods: To begin to fill this gap, the authors conducted a secondary analysis of data from the 2013–2014 administration of the National Health and Nutrition Examination Survey, comparing alcohol and drug use between participants based on their reported hearing status, i.e., D/HH or hearing. Results: Findings suggest that the overall lifetime prevalence of alcohol and drug use does not differ based on hearing status, and that D/HH and hearing adolescents begin using cannabis on a similar timeline. However, findings also revealed that D/HH respondents were more likely to have been regular cannabis users and heavy alcohol users than hearing respondents. In other words, when D/HH individuals use substances, they tend to be heavy users. Conclusions: These findings stress the importance of directing resources to the prevention and treatment of heavy alcohol use in the D/HH population, given that binge drinking is associated with a number of health problems and social consequences. Additionally, the continuation of this empirical work is rather urgent given recent legislative changes regarding cannabis use. D/HH individuals possess a number of risk factors for substance use disorder and, as such, may be more greatly impacted by these legislative changes than individuals from the general US population. It is imperative that this impact be captured by future research efforts in order to inform the development of prevention and intervention efforts for the traditionally underserved D/HH population.
Relation of Sex Hormone Levels With Prevalent and 10-Year Change in Aortic Distensibility Assessed by MRI: The Multi-Ethnic Study of Atherosclerosis
Authors: Subramanya Vinita , Ambale-Venkatesh Bharath , Ohyama Yoshiaki , Zhao Di , Nwabuo Chike C , Post Wendy S , Guallar Eliseo , Ouyang Pamela , Shah Sanjiv J , Allison Matthew A , Ndumele Chiadi E , Vaidya Dhananjay , Bluemke David A , Lima Joao A , Michos Erin D
Published: February 2018

BACKGROUND

Women experience a steeper decline in aortic elasticity related to aging compared to men. We examined whether sex hormone levels were associated with ascending aortic distensibility (AAD) in the Multi-Ethnic Study of Atherosclerosis.

METHODS

We studied 1,345 postmenopausal women and 1,532 men aged 45–84 years, who had serum sex hormone levels, AAD measured by phase-contrast cardiac magnetic resonance imaging, and ejection fraction>50% at baseline. Among these participants, 457 women and 548 men returned for follow-up magnetic resonance imaging 10-years later. Stratified by sex, and using mixed effects linear regression methods, we examined associations of sex hormones (as tertiles) with baseline and annual change in log-transformed AAD (mm Hg−110−3), adjusting for demographics, body size, lifestyle factors, mean arterial pressure, heart rate, hypertensive medication use (and in women, for hormone therapy use and years since menopause).

RESULTS

The mean (SD) age was 65 (9) for women and 62 (10) years for men. AAD was lower in women than men (P < 0.001). In adjusted cross-sectional analysis, the highest tertile of free testosterone (compared to lowest) in women was significantly associated with lower AAD [−0.10 (−0.19, −0.01)] and the highest tertile of estradiol in men was associated with greater AAD [0.12 (0.04, 0.20)]. There were no associations of sex hormones with change in AAD over 10 years, albeit in a smaller sample size.

CONCLUSIONS

Lower free testosterone in women and higher estradiol in men were associated with greater aortic distensibility at baseline, but not longitudinally. Sex hormone levels may account for differences in AAD between women and men.
STAR Chimeric Post for rapid detection of circular RNA and fusion transcripts
Authors: Akers Nicholas K , Schadt Eric E , Losic Bojan
Published: February 2018

Motivation

The biological relevance of chimeric RNA alignments is now well established. Chimera arising as chromosomal fusions are often drivers of cancer and recently discovered circular RNA (circRNA) are only now being characterized. While software already exists for fusion discovery and quantitation, high false positive rates and high run-times hamper scalable fusion discovery on large datasets. Furthermore, software available for circRNA detection and quantification is limited.

Results

Here, we present STAR Chimeric Post (STARChip), a novel software package that processes chimeric alignments from the STAR aligner and produces annotated circRNA and high precision fusions in a rapid, efficient and scalable manner that is appropriate for high dimensional medical omics datasets.

Availability and implementation

STARChip is available at https://github.com/LosicLab/STARChip.

Supplementary information

Supplementary data are available at Bioinformatics online.
Frontoparietal Tracts Linked to Lateralized Hand Preference and Manual Specialization
Authors: Howells Henrietta , Thiebaut de Schotten Michel , Dell’Acqua Flavio , Beyh Ahmad , Zappalà Giuseppe , Leslie Anoushka , Simmons Andrew , Murphy Declan G , Catani Marco
Published: February 2018

Humans show a preference for using the right hand over the left for tasks and activities of everyday life. While experimental work in non-human primates has identified the neural systems responsible for reaching and grasping, the neural basis of lateralized motor behavior in humans remains elusive. The advent of diffusion imaging tractography for studying connectional anatomy in the living human brain provides the possibility of understanding the relationship between hemispheric asymmetry, hand preference, and manual specialization. In this study, diffusion tractography was used to demonstrate an interaction between hand preference and the asymmetry of frontoparietal tracts, specifically the dorsal branch of the superior longitudinal fasciculus, responsible for visuospatial integration and motor planning. This is in contrast to the corticospinal tract and the superior cerebellar peduncle, for which asymmetry was not related to hand preference. Asymmetry of the dorsal frontoparietal tract was also highly correlated with the degree of lateralization in tasks requiring visuospatial integration and fine motor control. These results suggest a common anatomical substrate for hand preference and lateralized manual specialization in frontoparietal tracts important for visuomotor processing.
Current Predictive Indices and Nomograms To Enable Personalization of Radiation Therapy for Patients With Secondary Malignant Neoplasms of the Central Nervous System: A Review
Authors: Gilbride Lucas , Siker Malika , Bovi Joseph , Gore Elizabeth , Schultz Christopher , Hall William A
Published: February 2018

The proper treatment of brain metastases continues to be a challenge for oncologists given the variability of individual patients’ prognoses and the variety of treatment options available to address brain metasteses. There have been efforts since the 1990s to develop prognostic indices and nomograms to help clinicians determine the best approach for individuals with secondary malignant neoplasms of the central nervous system. A literature search was performed to identify the existing prognostic tools published between January 1995 and January 2017. While there have been several reported indices, many are limited by the number of patients analyzed or lack of generalizability. The most robust prognostic tools available are the Disease Specific Graded Prognostic Assessment and the Barnholtz-Sloan nomogram, both of which have online tools available to help clinicians. While these tools are helpful in stratifying different patients’ outcomes, they are limited by their retrospective nature and likely underestimate survival in the modern era, where there is a rapidly growing arsenal of systemic agents available to patients with metastatic disease.
Temporal Delays Along the Neurosurgical Care Continuum for Traumatic Brain Injury Patients at a Tertiary Care Hospital in Kampala, Uganda
Authors: Vaca Silvia D , Kuo Benjamin J , Nickenig Vissoci Joao Ricardo , Staton Catherine A , Xu Linda W , Muhumuza Michael , Ssenyonjo Hussein , Mukasa John , Kiryabwire Joel , Rice Henry E , Grant Gerald A , Haglund Michael M
Published: February 2018

BACKGROUND

Significant care continuum delays between acute traumatic brain injury (TBI) and definitive surgery are associated with poor outcomes. Use of the “3 delays” model to evaluate TBI outcomes in low- and middle-income countries has not been performed.

OBJECTIVE

To describe the care continuum, using the 3 delays framework, and its association with TBI patient outcomes in Kampala, Uganda.

METHODS

Prospective data were collected for 563 TBI patients presenting to a tertiary hospital in Kampala from 1 June to 30 November 2016. Four time intervals were constructed along 5 time points: injury, hospital arrival, neurosurgical evaluation, computed tomography (CT) results, and definitive surgery. Time interval differences among mild, moderate, and severe TBI and their association with mortality were analyzed.

RESULTS

Significant care continuum differences were observed for interval 3 (neurosurgical evaluation to CT result) and 4 (CT result to surgery) between severe TBI patients (7 h for interval 3 and 24 h for interval 4) and mild TBI patients (19 h for interval 3 and 96 h for interval 4). These postarrival delays were associated with mortality for mild (P = .05) and moderate TBI (P = .03) patients. Significant hospital arrival delays for moderate TBI patients were associated with mortality (P = .04).

CONCLUSION

Delays for mild and moderate TBI patients were associated with mortality, suggesting that quality improvement interventions could target current triage practices. Future research should aim to understand the contributors to delays along the care continuum, opportunities for more effective resource allocation, and the need to improve prehospital logistical referral systems.
Positive Effect of Liposomal Amikacin for Inhalation on Mycobacterium abcessus in Cystic Fibrosis Patients
Authors: Caimmi Davide , Martocq Nicolas , Trioleyre Delphine , Guinet Catherine , Godreuil Sylvain , Daniel Thomas , Chiron Raphael
Published: February 2018

Mycobacterium abscessus is difficult to eradicate. At the Montpellier CF Center, we prescribed liposomal amikacin for inhalation to 5 patients with M abscessus infection. The 3 patients who completed the treatment did not have any respiratory exacerbation, showed negative cultures for M abscessus in their sputum, and stabilized their spirometric functions.
Acute Epiglottitis in the Immunocompromised Host: Case Report and Review of the Literature
Authors: Chen Cheng , Natarajan Mukil , Bianchi David , Aue Georg , Powers John H
Published: February 2018

We present a case of acute epiglottitis in a 16-year-old with severe aplastic anemia. He was admitted with a history suggestive of a severe upper airway infection and an absolute neutrophil count of 0 per cubic millimeter. Despite his immunocompromised state, he presented with the classical signs and symptoms of epiglottitis. We review here the presentation and comorbidities of immunocompromised patients with epiglottitis. In addition, the appropriate choice of empirical antibiotic therapy is important for the management of epiglottitis in immunocompromised patients, especially in the post–Haemophilus influenza type B vaccination era. In our patient, Enterobacter cloacae was isolated from endoscopically directed throat cultures, and treatment was successful without the need for intubation. The current literature suggests that in immunocompromised patients, particularly those who are neutropenic, there is a potentially wide range of organisms, both bacterial and fungal, that may play a role in the pathology of acute epiglottitis.
Dynamics of Colonization of Streptococcus pneumoniae Strains in Healthy Peruvian Children
Authors: Nelson Kristin N , Grijalva Carlos G , Chochua Sopio , Hawkins Paulina A , Gil Ana I , Lanata Claudio F , Griffin Marie R , Edwards Kathryn M , Klugman Keith P , Vidal Jorge E
Published: February 2018

Background

Although asymptomatic carriage of Streptococcus pneumoniae (Spn) is common, acquisition of the bacteria is the first step in disease pathogenesis. We examined the effect of introduction of the 7-valent pneumococcal vaccine on Spn carriage patterns in a cohort of Peruvian children.

Methods

We used data from a prospective cohort study that collected monthly nasopharyngeal samples from children under 3 years of age. Spn isolates were serotyped using Quellung reactions, and bacterial density was determined by quantitative polymerase chain reaction. Changes in Spn carriage patterns, including the rate of carriage and number and density of serotypes carried over time, were evaluated before (2009) and after widespread vaccination with PCV7 (2011). Using all pneumococcal detections from each child and year, we identified serotypes that were present both at first and last detection as “persisters” and serotypes that replaced a different earlier type and were detected last as “recolonizers.”

Results

Ninety-two percent (467/506) of children in 2009 and 89% (451/509) in 2011 carried Spn at least once. In 2009 and 2011, rates of carriage were 9.03 and 9.04 Spn detections per person-year, respectively. In 2009, 23F, a serotype included in PCV7, was the only type identified as a persister and 6A, 15B, and 19A were identified as recolonizer serotypes. In 2011, 6B and 7C were persister serotypes and 13 was a frequent recolonizer serotype.

Conclusions

Overall Spn carriage among children under 3 in Peru was similar before and after introduction of PCV7; however, serotype-specific rates and longitudinal carriage patterns have shifted.
Intervention Packages to Reduce the Impact of HIV and HCV Infections Among People Who Inject Drugs in Eastern Europe and Central Asia: A Modeling and Cost-effectiveness Study
Authors: Mabileau Guillaume , Scutelniciuc Otilia , Tsereteli Maia , Konorazov Ivan , Yelizaryeva Alla , Popovici Svetlana , Saifuddin Karimov , Losina Elena , Manova Manoela , Saldanha Vinay , Malkin Jean-Elie , Yazdanpanah Yazdan
Published: February 2018

Background

We evaluated the effectiveness and cost-effectiveness of interventions targeting hepatitis C virus (HCV) and HIV infections among people who inject drugs (PWID) in Eastern Europe/Central Asia. We specifically considered the needle-syringe program (NSP), opioid substitution therapy (OST), HCV and HIV diagnosis, antiretroviral therapy (ART), and/or new HCV treatment (direct acting antiviral [DAA]) in Belarus, Georgia, Kazakhstan, Republic of Moldova, and Tajikistan.

Methods

We developed a deterministic dynamic compartmental model and evaluated the number of infections averted, costs, and incremental cost-effectiveness ratios (ICERs) of interventions. OST decreased frequencies of injecting by 85% and NSP needle sharing rates by 57%; ART was introduced at CD4 <350 and DAA at fibrosis stage ≥F2 at a $2370 to $23 280 cost.

Results

Increasing NSP+OST had a high impact on transmissions (infections averted in PWID: 42% in Tajikistan to 55% in Republic of Moldova for HCV; 30% in Belarus to 61% in Kazakhstan for HIV over 20 years). Increasing NSP+OST+ART was very cost-effective in Georgia (ICER = $910/year of life saved [YLS]), and was cost-saving in Kazakhstan and Republic of Moldova. NSP+OST+ART and HIV diagnosis was very cost-effective in Tajikistan (ICER = $210/YLS). Increasing the coverage of all interventions was always the most effective strategy and was cost-effective in Belarus and Kazakhstan (ICER = $12 960 and $21 850/YLS); it became cost-effective/cost-saving in all countries when we decreased DAA costs.

Conclusion

Increasing NSP+OST coverage, in addition to ART and HIV diagnosis, had a high impact on both epidemics and was very cost-effective and even cost-saving. When HCV diagnosis was improved, increased DAA averted a high number of new infections if associated with NSP+OST.
Risk-Based Hepatitis C Screening in Pregnancy Is Less Reliable Than Universal Screening: A Retrospective Chart Review
Authors: Boudova Sarah , Mark Katrina , El-Kamary Samer S
Published: February 2018

Current guidelines recommend only hepatitis C virus (HCV) risk-based screening during pregnancy. We examined screening practices at a major medical center and found inconsistent risk-based screening and the presence of HCV among women with no known risk factors. We make a case for the implementation of universal HCV screening during pregnancy.
Estimation of adaptive ventilation success and failure using polysomnogram and outpatient therapy biomarkers
Authors: Gunn Stacey , Naik Sreelatha , Bianchi Matt Travis , Thomas Robert Joseph
Published: February 2018

Study Objectives

Adaptive servo-ventilation (ASV) devices provide anticyclic pressure support for the treatment of central and/or complex sleep apnea, including heart failure patients. Variability in responses in the clinic and negative clinical trials motivated assessment of standard and novel signal biomarkers for ASV efficacy.

Methods

Multiple clinical databases were queried to assess potential signal biomarkers of ASV effectiveness, including the following: (1) attended laboratory adaptive ventilation titrations: 108, of which 66 had mainstream ETCO2 measurements; (2) AirView data in 98 participants, (3) complete data, from diagnostic polysomnogram (PSG) through review and prospective analysis of on-therapy data using SleepyHead freeware in 44 participants; and (4) hemodynamic data in the form of beat-to-beat blood pressure during ASV titration, using a Finometer in five participants.

Results

Signal biomarkers of reduced ASV efficacy were noted as follows: (1) an arousal index which markedly exceeded the respiratory event index during positive pressure titration; (2) persistent pressure cycling during long-term ASV therapy, visible in online review systems or reviewing data using freeware; (3) the ASV-associated pressure cycling induced arousals, sleep fragmentation, and blood pressure surges; and (4) elevated ratios of 95th percentile to median tidal volume, minute ventilation, and respiratory rate were associated with pressure cycling. High intraclass coefficients (>0.8) for machine apnea–hypopnea index and other extractable metrics were consistent with stability of patterns over multiple nights of use. Global clinical outcomes correlated negatively with pressure cycling.

Conclusions

Potential polysomnographic- and device-related signal biomarkers of ASV efficacy are described and may allow improved estimation of therapeutic effectiveness of adaptive ventilation.
Liquefaction of the brain following stroke shares a similar molecular and morphological profile with atherosclerosis and mediates secondary neurodegeneration in an osteopontin dependent mechanism
Authors: Chung Amanda G. , Frye Jennifer B. , Zbesko Jacob C. , Constantopoulos Eleni , Hayes Megan , Figueroa Anna G. , Becktel Danielle A. , Day W. Antony , Konhilas John P. , McKay Brian S. , Nguyen Thuy-Vi V. , Doyle Kristian P.
Published: February 2018

Here we used mouse models of heart and brain ischemia to compare the inflammatory response to ischemia in the heart, a protein rich organ, to the inflammatory response to ischemia in the brain, a lipid rich organ. We report that ischemia-induced inflammation resolves between 1 and 4 weeks in the heart compared to between 8 and 24 weeks in the brain. Importantly, we discovered that a second burst of inflammation occurs in the brain between 4 and 8 weeks following ischemia, which coincided with the appearance of cholesterol crystals within the infarct. This second wave shares a similar cellular and molecular profile with atherosclerosis and is characterized by high levels of osteopontin (OPN) and matrix metalloproteinases (MMPs). In order to test the role of OPN in areas of liquefactive necrosis, OPN-/-mice were subjected to brain ischemia. We found that at 7 weeks following stroke, the expression of pro-inflammatory proteins and MMPs was profoundly reduced in the infarct of the OPN-/-mice, although the number of cholesterol crystals was increased. OPN-/-mice exhibited faster recovery of motor function and a higher number of neuronal nuclei (NeuN) positive cells in the peri-infarct area at 7 weeks following stroke. Based on these findings we propose that the brain liquefies after stroke because phagocytic cells in the infarct are unable to efficiently clear cholesterol rich myelin debris, and that this leads to the perpetuation of an OPN-dependent inflammatory response characterized by high levels of degradative enzymes.

Significance Statement

The inflammatory response to ischemia in the brain is different to the response to ischemic injury in other organs. In the brain, and for unknown reasons, dead tissue liquefies in response to ischemia by the process of liquefactive necrosis. However, the data we present here demonstrate that there is overlap between the pathophysiology of liquefactive necrosis and atherosclerosis. Specifically, we show that chronic stroke infarcts contain foamy macrophages, cholesterol crystals, high levels of OPN and MMPs, and a similar cytokine profile to atherosclerosis. Therefore, because cholesterol is a central component of myelin, liquefactive necrosis in response to stroke may be caused by an inflammatory response to cholesterol-rich myelin debris that is driven in large part by OPN and MMPs.
Using maximum entropy production to describe microbial biogeochemistry over time and space in a meromictic pond
Authors: Vallino Joseph J. , Huber Julie A.
Published: February 2018

The maximum entropy production (MEP) conjecture posits that systems with many degrees of freedom will likely organize to maximize the rate of free energy dissipation. Previous work indicates that biological systems can outcompete abiotic systems by maximizing free energy dissipation over time by utilizing temporal strategies acquired and refined by evolution, and over space via cooperation. In this study, we develop an MEP model to describe biogeochemistry observed in Siders Pond, a phosphate limited meromictic system located in Falmouth, MA that exhibits steep chemical gradients due to density-driven stratification that supports anaerobic photosynthesis as well as microbial communities that catalyze redox cycles involving O, N, S, Fe and Mn. The MEP model uses a metabolic network to represent microbial redox reactions, where biomass allocation and reaction rates are determined by solving an optimization problem that maximizes entropy production over time and a 1D vertical profile constrained by an advection-dispersion-reaction model. We introduce a new approach for modeling phototrophy and explicitly represent aerobic photoautotrophs, anoxygenic photoheterotrophs and anaerobic photoautotrophs. The metabolic network also includes reactions for heterotrophic bacteria, sulfate reducing bacteria, sulfide oxidizing bacteria and aerobic and anaerobic grazers. Model results were compared to observations of biogeochemical constituents collected over a 24 hour period at 8 depths at a single 15 m deep station in Siders Pond. Maximizing entropy production over long (3 d) intervals produced results more similar to field observations than short (0.25 d) interval optimizations, which support the importance of temporal strategies for maximizing entropy production over time. Furthermore, we found that entropy production must be maximized locally instead of globally where energy potentials are degraded quickly by abiotic processes, such as light absorption by water. This combination of field observations with modeling results show that microbial systems in nature can be accurately described by the maximum entropy production conjecture applied over time and space.
The clinician impact and financial cost to the NHS of litigation over pregabalin: a cohort study in English primary care
Authors: Croker Richard , Smyth Darren , Walker Alex J , Goldacre Ben
Published: February 2018

Objectives

Following litigation over pregabalin’s second-use medical patent for neuropathic pain NHS England were required by the court to instruct GPs to prescribe the branded form (Lyrica) for pain. Pfizer’s patent was found invalid in 2015; a ruling subject to ongoing appeals. If the Supreme Court appeal in February 2018 is unsuccessful, the NHS can reclaim excess prescribing costs. We set out to describe the variation in prescribing of pregabalin as branded Lyrica, geographically and over time; to determine how clinicians responded to the NHS England instruction to GPs; and to model excess costs to the NHS attributable to the legal judgments.

Setting

English primary care

Participants

English general practices

Primary and secondary outcome measures

Variation in prescribing of branded Lyrica across the country before and after the NHS England instruction, by practice and by Clinical Commissioning Group (CCG); excess prescribing costs.

Results

The proportion of pregabalin prescribed as Lyrica increased, from 0.3% over six months before the NHS England instruction (September 2014-February 2015) to 25.7% afterwards (April - September 2015). Although 70% of pregabalin is estimated to be for neuropathic pain, only 11.6% of practices prescribed Lyrica at this level; the median proportion prescribed as Lyrica was 8.8% (IQR 1.1-41.9%). If pregabalin had come entirely off patent in September 2015, and Pfizer had not appealed, we estimate the NHS would have spent £502m less on pregabalin to July 2017.

Conclusion

NHS England instructions to GPs regarding branded prescription of pregabalin were widely ignored, and have created much debate around clinical independence in prescribing. Protecting revenue from “skinny labels” will pose a challenge. If Pfizer’s final appeal on the patent is unsuccessful the NHS can seek reimbursement of excess pregabalin prescribing costs, potentially £502m.
Stability of representational geometry across a wide range of fMRI activity levels
Authors: Arbuckle Spencer A. , Yokoi Atsushi , Pruszynski J. Andrew , Diedrichsen Jörn
Published: February 2018

Fine-grained activity patterns, as measured with functional magnetic resonance imaging (fMRI), are thought to reflect underlying neural representations. Multivariate analysis techniques, such as representational similarity analysis (RSA), can be used to test models of brain representation by quantifying the representational geometry (the collection of pair-wise dissimilarities between activity patterns). One important caveat, however, is that non-linearities in the coupling between neural activity and the fMRI signal may lead to significant distortions in the representational geometry estimated from fMRI activity patterns. Here we tested the stability of representational dissimilarity measures in primary sensory-motor (S1 and M1) and early visual regions (V1/V2) across a large range of activation levels. Subjects were visually cued with different letters to perform single finger presses with one of the 5 fingers at a rate of 0.3-2.6 Hz. For each stimulation frequency, we quantified the difference between the 5 activity patterns in M1, S1, and V1/V2. We found that the representational geometry remained stable, even though the average activity increased over a large dynamic range. These results indicate that the representational geometry of fMRI activity patterns can be reliably assessed, largely independent of the average activity in the region. This has important methodological implications for RSA and other multivariate analysis approaches that use the representational geometry to make inferences about brain representations.
BAX requires VDAC2 to mediate apoptosis and to limit tumor development
Authors: Chin Hui San , van Delft Mark F. , Ninnis Robert L. , Li Mark X. , Tan Iris K. L. , Reljic Boris , Scicluna Kristen , Dagley Laura F. , Sandow Jarrod J. , Kelly Gemma L. , Chappaz Stephane , Khaw Seong L. , Chang Catherine , Webb Andrew , Hockings Colin , Hall Cathrine M. , Kueh Andrew J. , Ryan Michael T. , Kluck Ruth M. , Bouillet Philippe , Herold Marco J. , Gray Daniel H. D. , Huang David C. S. , Dewson Grant
Published: February 2018

Intrinsic apoptosis is critical for normal physiology including the prevention of tumor formation. BAX and BAK are essential for mediating this process and for the cytotoxic action of many anticancer drugs. BAX and BAK are thought to act in a functionally redundant manner and are considered to be regulated similarly. From an unbiased genome-wide CRISPR/Cas9 screen, we identified VDAC2 (voltage-dependent anion channel 2) as essential for BAX, but not BAK, to function. The genetic deletion of VDAC2 abrogated the association of BAX and BAK with mitochondrial complexes that contain VDAC1, VDAC2 and VDAC3. By disrupting its localization to mitochondria, BAX is rendered completely ineffective. Moreover, we defined an interface unique to VDAC2 that is required to drive BAX activity. Consequently, interfering with this interaction or deleting VDAC2 phenocopied the loss of BAX, including impairing the killing of tumor cells by anti-cancer agents such as the BCL-2 inhibitor venetoclax. Furthermore, the ability of BAX to prevent tumor formation was attenuated in the absence of VDAC2. Taken together, our studies show for the first time that BAX-mediated apoptosis, but not BAK-mediated apoptosis, is critically dependent on VDAC2, hence revealing the differential regulation of BAX and BAK.
A grow-and-lock model for the control of flagellum length in trypanosomes
Authors: Bertiaux Eloïse , Morga Benjamin , Blisnick Thierry , Rotureau Brice , Bastin Philippe
Published: February 2018

Several models have been proposed to explain how eukaryotic cells control the length of their cilia and flagella. Here, we investigated this process in the protistTrypanosoma brucei, an excellent system for cells with stable cilia like photoreceptors or spermatozoa. We show that the total amount of intraflagellar transport material (IFT, the machinery responsible for flagellum construction) increases during flagellum elongation, consistent with constant delivery of precursors and the previously reported linear growth. Reducing the IFT frequency by RNAi knockdown of the IFT kinesin motors slows down the elongation rate and results in the assembly of shorter flagella. These keep on elongating after cell division but fail to reach the normal length. This failure is neither due to an absence of precursors nor to a morphogenetic control by the cell body. We propose that the flagellum is locked after cell division, preventing further elongation or shortening. This is supported by the fact that subsequent increase in the IFT rate does not lead to further elongation. The distal tip FLAM8 protein was identified as a marker for the locking event. It is initiated prior cell division, leading to an arrest of elongation in the daughter cell. Here, we propose a new model termed grow-and-lock where the flagellum elongates until a locking event takes place in a timely defined manner hence fixing length. Alteration in the growth rate and/or in the timing of the locking event would lead to the formation of flagella of different lengths.
DNA sequence context controls the binding and processivity of the T7 DNA primase
Authors: Afek Ariel , Ilic Stefan , Horton John , Lukatsky David B. , Gordan Raluca , Akabayov Barak
Published: February 2018

Primases are key enzymes involved in DNA replication. They act on single-stranded DNA, and catalyze the synthesis of short RNA primers used by DNA polymerases. Here, we investigate the DNA-binding and activity of the bacteriophage T7 primase using a new workflow calledHigh-ThroughputPrimaseProfiling (HTPP). Using a unique combination of high-throughput binding assays and biochemical analyses, HTPP reveals a complex landscape of binding specificity and functional activity for the T7 primase, determined by sequences flanking the primase recognition site. We identified specific features, such as G/T-rich flanks, which increase primase-DNA binding up to 10-fold and, surprisingly, also increase the length of newly formed RNA (up to 3-fold). To our knowledge, variability in primer length has not been reported for this primase. We expect that applying HTPP to additional enzymes will reveal new insights into the effects of DNA sequence composition on the DNA recognition and functional activity of primases.
Regulation of ATR activity by the RNA polymerase II phosphatase PNUTS-PP1
Authors: Landsverk Helga B. , Sandquist Lise E. , Rødland Gro Elise , Grallert Beata , Trinkle-Mulcahy Laura , Syljuåsen Randi G.
Published: February 2018

Ataxia telangiectasia mutated and Rad3-related (ATR) kinase is a key factor activated by DNA damage and replication stress. Here, we show that ATR signaling is increased in human cells after depletion of the RNAPII phosphatase PNUTS-PP1, which dephosphorylates RNAPII on Ser 5 of its carboxy-terminal domain (CTD) (pRNAPII S5). Increased ATR signaling was observed in the presence and absence of ionizing radiation or replication stress and even in G1 phase after depletion of PNUTS. Vice versa, ATR signaling was reduced, in a PNUTS dependent manner, after inhibition of the CDK7 kinase mediating pRNAPII S5. Furthermore, CDC73, a well-known RNAPII-CTD binding protein, was required for the high ATR signaling after depletion of PNUTS and co-immunoprecipitated with RNAPII and ATR. These results suggest a novel pathway involving RNAPII, PNUTS-PP1 and CDC73 in ATR signaling and give new insight into the diverse functions of ATR.
Myosin1D is an evolutionarily conserved determinant of animal Left/Right asymmetry
Authors: Juan Thomas , Géminard Charles , Coutelis Jean-Baptiste , Cerezo Delphine , Polès Sophie , Noselli Stéphane , Fürthauer Maximilian
Published: February 2018

The establishment of Left/Right (LR) asymmetry is fundamental to animal development. While the pathways governing antero-posterior and dorso-ventral patterning are well conserved among different phyla, divergent mechanisms have been implicated in the specification of LR asymmetry in vertebrates and invertebrates. A cilia-driven, directional fluid flow is important for symmetry breaking in numerous vertebrates, including zebrafish1–10. Alternatively, LR asymmetry can be established independently of motile cilia, notably through the intrinsic chirality of the acto-myosin cytoskeleton11–18. Here we show that MyosiniD (Myo1D), which has been previously identified as a key determinant of LR asymmetry in Drosophila12,13, is essential for the formation and the function of the zebrafish LR Organizer (LRO). We show that Myo1D controls the polarity of LRO cilia and interacts functionally with the Planar Cell Polarity (PCP) gene VanGogh-like2 (Vangl2)19, to promote the establishment of a functional LRO flow. Our findings identify Myo1D as the first evolutionarily conserved determinant of LR asymmetry, and show that functional interactions between Myo1D and PCP are central to the establishment of animal LR asymmetry.
Urban crisis change efforts: the NAB and NUC
Authors: Singleton Laura G.
Published: February 2018

Purpose

This study aims to compare the National Alliance of Businessmen and the National Urban Coalition, two change efforts spawned during the 1960’s US Urban Crisis, in which businesses took a central role to address urban problems, particularly through expanding opportunities for African-Americans.

Design/methodology/approach

This is a historical comparative case study developed through research utilizing published resources and archival material.

Findings

Neither organization clearly achieved its initial goals, with each migrating toward the end of its existence away from business-related goals to focus on public education. Potential causes include economic obstacles, a heroic conception of change that fostered overcommitment, and conflicting institutional logics in the organization’s missions, both of which were intertwined with governmental objectives from their foundings. However, the period shows overall changes in social awareness by business, in which these organizations played a part, and efforts by today’s businesses to respond to racial tensions in cities display learning from these predecessor organizations.

Research limitations/implications

A significant dependence on published sources limits the depth of insight versus accessing organizational archives; however, it does offer a similar basis for information on both organizations to facilitate comparisons.

Practical implications

The structural vulnerabilities of these organizations can present lessons for organizations hoping to pursue similar change through business partnerships today.

Social implications

The racial tensions continuing in the USA today display parallel the challenges of the 1960s, making learning from these precedents valuable.

Originality/value

This study offers a comparative view of the NAB and NUC throughout their history, which has not previously been provided.
Continuity and change in the Sheffield armaments industry 1919-1930
Authors: Corker Chris
Published: February 2018

Purpose

This article aims to explore the impact of the Great War on the Sheffield armaments industry through the use of four company case studies in Thomas Firth, John Brown, Cammell Laird and Hadfields. It charts the evolving situation the armaments companies found themselves in after the end of the conflict and the uncertain external environment they had to engage with. The article also examines the stagnant nature of armaments companies’ boards of directors in the 1920s and the ultimate rationalisation of the industry at the close of the decade.

Design/methodology/approach

The research design is based around a close examination of the surviving manuscript records of each of the companies included, the records of the speeches recorded by chairpersons at annual meetings and some governmental records.

Findings

The article concludes by outlining how the end of the Great War continued to affect the industry for the following decade and the complex evolving situation with a changing external environment and continuity of management internally ultimately leading to mergers in the industry.

Originality/value

This article uses a number of underused manuscript records to examine the Sheffield armaments industry and explores the effect of a global mega event in the Great War on one of the most technologically advanced industries of the period.
Challenges of listening to an autistic pupil in a person‐centred planning meeting
Authors: Barnard‐Dadds Tracey , Conn Carmel
Published: February 2018

A consensus is emerging on the need to use person‐centred planning (PCP) as an approach to the identification of educational learning needs and goals for pupils with special needs, including those on the autism spectrum. The aim of this study was to analyse the interactions of participants in one PCP meeting, specifically the nature of participation of the focus pupil with autism and the way in which this was supported by staff members and parents. Conversation analysis was used to investigate interactional turns and the way in which social actions in the meeting unfolded. Findings are that, despite encouragement and prompting by adult participants, the contribution of the pupil with autism was minimal throughout, except for the mention of one potentially painful issue. The suitability of PCP meetings as a forum for the exploration of difficult issues is discussed and the issue of prior preparation for meetings by child and adult participants is raised with reference to the management of autism as a transactional disability.