bluuebunny/crossref_metadata_2025 huggingface dataset:
Optimising case detection within UK electronic health records: use of multiple linked databases for detecting liver injury
Authors: Wing Kevin , Bhaskaran Krishnan , Smeeth Liam , van Staa Tjeerd P , Klungel Olaf H , Reynolds Robert F , Douglas Ian
Published: September 2016

Objectives

We aimed to create a ‘multidatabase’ algorithm for identification of cholestatic liver injury using multiple linked UK databases, before (1) assessing the improvement in case ascertainment compared to using a single database and (2) developing a new single-database case-definition algorithm, validated against the multidatabase algorithm.

Design

Method development for case ascertainment.

Setting

Three UK population-based electronic health record databases: the UK Clinical Practice Research Datalink (CPRD), the UK Hospital Episodes Statistics (HES) database and the UK Office of National Statistics (ONS) mortality database.

Participants

16 040 people over the age of 18 years with linked CPRD–HES records indicating potential cholestatic liver injury between 1 January 2000 and 1 January 2013.

Primary outcome measures

(1) The number of cases of cholestatic liver injury detected by the multidatabase algorithm. (2) The relative contribution of each data source to multidatabase case status. (3) The ability of the new single-database algorithm to discriminate multidatabase algorithm case status.

Results

Within the multidatabase case identification algorithm, 4033 of 16 040 potential cases (25%) were identified as definite cases based on CPRD data. HES data allowed possible cases to be discriminated from unlikely cases (947 of 16 040, 6%), but only facilitated identification of 1 definite case. ONS data did not contribute to case definition. The new single-database (CPRD-only) algorithm had a very good ability to discriminate multidatabase case status (area under the receiver operator characteristic curve 0.95).

Conclusions

CPRD–HES–ONS linkage confers minimal improvement in cholestatic liver injury case ascertainment compared to using CPRD data alone, and a multidatabase algorithm provides little additional information for validation of a CPRD-only algorithm. The availability of laboratory test results within CPRD but not HES means that algorithms based on CPRD–HES-linked data may not always be merited for studies of liver injury, or for other outcomes relying primarily on laboratory test results.
Cohort profile: cerebral palsy in the Norwegian and Danish birth cohorts (MOBAND-CP)
Authors: Tollånes Mette C , Strandberg-Larsen Katrine , Forthun Ingeborg , Petersen Tanja Gram , Moster Dag , Andersen Anne-Marie Nybo , Stoltenberg Camilla , Olsen Jørn , Wilcox Allen J
Published: September 2016

Purpose

The purpose ofMOthers andBAbies inNorway andDenmark cerebral palsy (MOBAND-CP) was to study CP aetiology in a prospective design.

Participants

MOBAND-CP is a cohort of more than 210 000 children, created as a collaboration between the world's two largest pregnancy cohorts—the Norwegian Mother and Child Cohort study (MoBa) and the Danish National Birth Cohort. MOBAND-CP includes maternal interview/questionnaire data collected during pregnancy and follow-up, plus linked information from national health registries.

Findings to date

Initial harmonisation of data from the 2 cohorts has created 140 variables for children and their mothers. In the MOBAND-CP cohort, 438 children with CP have been identified through record linkage with validated national registries, providing by far the largest such sample with prospectively collected detailed pregnancy data. Several studies investigating various hypotheses regarding CP aetiology are currently on-going.

Future plans

Additional data can be harmonised as necessary to meet requirements of new projects. Biological specimens collected during pregnancy and at delivery are potentially available for assay, as are results from assays conducted on these specimens for other projects. The study size allows consideration of CP subtypes, which is rare in aetiological studies of CP. In addition, MOBAND-CP provides a platform within the context of a merged birth cohort of exceptional size that could, after appropriate permissions have been sought, be used for cohort and case-cohort studies of other relatively rare health conditions of infants and children.
Improving communication between phlebotomists and doctors: a quality improvement project
Authors: Saunsbury Emma , Howarth Gabrielle
Published: September 2016

Blood tests are a seemingly basic investigation, but are often a vital part of directing patient management. Despite the importance of this everyday process, we indentified the potential for improvement of the current phlebotomy service in our hospital, as both junior doctors and phlebotomists reported a lack of communication and standardised practice across the wards. Resulting delays in obtaining blood test results can impact detrimentally on patient safety and management.

We designed a survey which highlighted inefficient handovers and discrepancies between wards as driving factors behind this. We therefore aimed to improve communication between phlebotomists and doctors, as well as the overall organisation of the service. This took the form of the “Phlebotomy Box,” a box file system offering a set location for blood stickers to be situated. The box concept was optimised on a series of medical and surgical wards, incorporating multidisciplinary feedback from relevant teams. We measured how many untaken bloods were handed over to medical staff continuously, both pre- and post implementation of the phlebotomy box.

Our baseline ward demonstrated poor handover rates of untaken bloods, ranging from 0% to 40%. This increased to a consistent 100% following introduction of the Phlebotomy Box and ongoing staff education. Once optimised, the box was trialled on a further two medical wards and one surgical ward, achieving 100% handover from an initial 0% to 67%. Quantitative improvement was also reflected qualitatively in widespread staff surveys, with overwhelmingly positive support and acceptance.

In summary, the Phlebotomy Box innovation has led to 100% of untaken bloods being effectively handed over. We have demonstrated a significant improvement in communication and efficiency within the phlebotomy service, with tangible benefits to patient care, as minimising time lags can prevent delays in clinical decisions. The phlebotomy box represents a simplistic, sustainable intervention that could be easily replicated in other Trusts.
Soluble urokinase plasminogen activator receptor (suPAR) in acute care: a strong marker of disease presence and severity, readmission and mortality. A retrospective cohort study
Authors: Rasmussen Line Jee Hartmann , Ladelund Steen , Haupt Thomas Huneck , Ellekilde Gertrude , Poulsen Jørgen Hjelm , Iversen Kasper , Eugen-Olsen Jesper , Andersen Ove
Published: September 2016

Objective

Soluble urokinase plasminogen activator receptor (suPAR) is an inflammatory biomarker associated with presence and progression of disease and with increased risk of mortality. We aimed to evaluate the unspecific biomarker suPAR as a prognostic marker in patients admitted to acute care.

Methods

This registry-based retrospective cohort study included 4343 consecutively admitted patients from the Acute Medical Unit at a large Danish university hospital. Time to readmission and death were analysed by multiple Cox regression. Results were reported as HRs for 30-day and 90-day follow-up.

Results

During 30-day follow-up, 782 patients (18.0%) were readmitted and 224 patients (5.2%) died. Comparing 30-day readmission and mortality between patients in the highest and lowest suPAR quartiles yielded HRs of 2.11 (95% CI 1.70 to 2.62) and 4.11 (95% CI 2.46 to 6.85), respectively, when adjusting for age, sex, Charlson score and C reactive protein. Area under the curve for receiver operating characteristics curve analysis of suPAR for 30-day mortality was 0.84 (95% CI 0.81 to 0.86). Furthermore, in the entire cohort, women had slightly higher suPAR compared with men, and suPAR was associated with age, admission time, admission to intensive care unit and Charlson score.

Conclusions

In this large unselected population of acute medical patients, suPAR is strongly associated with disease severity, readmission and mortality after adjusting for all other risk factors, indicating that suPAR adds information to established prognostic indicators. While patients with low suPAR levels have low risk of readmission and mortality, patients with high suPAR levels have a high risk of adverse events.
Stress activates pronociceptive endogenous opioid signalling in DRG neurons during chronic colitis
Authors: Guerrero-Alba Raquel , Valdez-Morales Eduardo E , Jimenez-Vargas Nestor N , Lopez-Lopez Cintya , Jaramillo-Polanco Josue , Okamoto Takanobu , Nasser Yasmin , Bunnett Nigel W , Lomax Alan E , Vanner Stephen J
Published: September 2016

Aims and background

Psychological stress accompanies chronic inflammatory diseases such as IBD, and stress hormones can exacerbate pain signalling. In contrast, the endogenous opioid system has an important analgesic action during chronic inflammation. This study examined the interaction of these pathways.

Methods

Mouse nociceptive dorsal root ganglia (DRG) neurons were incubated with supernatants from segments of inflamed colon collected from patients with chronic UC and mice with dextran sodium sulfate (cDSS)-induced chronic colitis. Stress effects were studied by adding stress hormones (epinephrine and corticosterone) to dissociated neurons or by exposing cDSS mice to water avoidance stress. Changes in excitability of colonic DRG nociceptors were measured using patch clamp and Ca2+imaging techniques.

Results

Supernatants from patients with chronic UC and from colons of mice with chronic colitis caused a naloxone-sensitive inhibition of neuronal excitability and capsaicin-evoked Ca2+responses. Stress hormones decreased signalling induced by human and mouse supernatants. This effect resulted from stress hormones signalling directly to DRG neurons and indirectly through signalling to the immune system, leading to decreased opioid levels and increased acute inflammation. The net effect of stress was a change endogenous opioid signalling in DRG neurons from an inhibitory to an excitatory effect. This switch was associated with a change in G protein-coupled receptor excitatory signalling to a pathway sensitive to inhibitors of protein kinase A-protein, phospholipase C-protein and G protein βϒ subunits.

Conclusions

Stress hormones block the inhibitory actions of endogenous opioids and can change the effect of opioid signalling in DRG neurons to excitation. Targeting these pathways may prevent heavy opioid use in IBD.
Improving Clinical and Translational Research Training: A Qualitative Evaluation of the Atlanta Clinical and Translational Science Institute KL2-Mentored Research Scholars Program
Authors: Comeau Dawn L , Escoffery Cam , Freedman Ariela , Ziegler Thomas R , Blumberg Henry M
Published: September 2016

A major impediment to improving the health of communities is the lack of qualified clinical and translational research (CTR) investigators. To address this workforce shortage, the National Institutes of Health (NIH) developed mechanisms to enhance the career development of CTR physician, PhD, and other doctoral junior faculty scientists including the CTR-focused K12 program and, subsequently, the KL2-mentored CTR career development program supported through the Clinical and Translational Science Awards (CTSAs). Our evaluation explores the impact of the K12/KL2 program embedded within the Atlanta Clinical and Translational Science Institute (ACTSI), a consortium linking Emory University, Morehouse School of Medicine and the Georgia Institute of Technology. We conducted qualitative interviews with program participants to evaluate the impact of the program on career development and collected data on traditional metrics (number of grants, publications). 46 combined K12/KL2 scholars were supported between 2002 and 2016. 30 (65%) of the 46 K12/KL2 scholars are women; 24 (52%) of the trainees are minorities, including 10 (22%) scholars who are members of an underrepresented minority group. Scholars reported increased research skills, strong mentorship experiences, and positive impact on their career trajectory. Among the 43 scholars who have completed the program, 39 (91%) remain engaged in CTR and received over $89 000 000 as principal investigators on federally funded awards. The K12/KL2 funding provided the training and protected time for successful career development of CTR scientists. These data highlight the need for continued support for CTR training programs for junior faculty.
Too good to intervene? Thrombectomy for large vessel occlusion strokes with minimal symptoms: an intention-to-treat analysis
Authors: Haussen Diogo C , Bouslama Mehdi , Grossberg Jonathan A , Anderson Aaron , Belagage Samir , Frankel Michael , Bianchi Nicolas , Rebello Leticia C , Nogueira Raul G
Published: September 2016

Introduction

The minimal stroke severity justifying endovascular intervention remains elusive; however, a significant proportion of patients presenting with large vessel occlusion (LVO) and mild symptoms subsequently decline and face poor outcomes.

Objective

To evaluate our experience with these patients by comparing best medical therapy with thrombectomy in an intention-to-treat analysis.

Methods

Analysis of prospectively collected data of all consecutive patients with National Institutes of Health Stroke Scale (NIHSS) score ≤5, LVO on CT angiography, and baseline modified Rankin Scale (mRS) score 0–2 from November 2014 to May 2016. After careful discussion with patients/family, a decision to pursue medical or interventional therapy was made. Deterioration (development of aphasia, neglect, and/or significant weakness) triggered reconsideration of thrombectomy. The primary outcome measure was NIHSS shift (discharge NIHSS score minus admission NIHSS score).

Results

Of the 32 patients qualifying for the study, 22 (69%) were primarily treated with medical therapy and 10 (31%) intervention. Baseline characteristics were comparable. Nine (41%) medically treated patients had subsequent deterioration requiring thrombectomy. Median time from arrival to deterioration was 5.2 hours (2.0–25.0). Successful reperfusion (modified Treatment in Cerebral Infarction 2b−3) was achieved in all 19 thrombectomy patients. The NIHSS shift significantly favored thrombectomy (−2.5 vs 0; p<0.01). The median NIHSS score at discharge was low with both thrombectomy (1 (0–3)) and medical therapy (2 (0.5–4.5)). 90-Day mRS 0–2 rates were 100% and 77%, respectively (p=0.15). Multivariable linear regression indicated that thrombectomy was independently associated with a beneficial NIHSS shift (unstandardized β −4.2 (95% CI −8.2 to −0.1); p=0.04).

Conclusions

Thrombectomy led to a shift towards a lower NIHSS in patients with LVO presenting with minimal stroke symptoms. Despite the overall perception that this condition is benign, nearly a quarter of patients primarily treated with medical therapy did not achieve independence at 90 days.
Application of visually based, computerised diagnostic decision support system in dermatological medical education: a pilot study
Authors: Chou Wan-Yi , Tien Peng-Tai , Lin Fang-Yu , Chiu Pin-Chi
Published: September 2016

Background

Medical education has shifted from memory-based practice to evidence-based decisions. The question arises: how can we ensure that all students get correct and systematic information? Visually based, computerised diagnostic decision support system (VCDDSS, VisualDx) may just fit our needs. A pilot study was conducted to investigate its role in medical education and clinical practice.

Methods

This was a prospective study, including one consultant dermatologist, 51 medical students and 13 dermatology residents, conducted in the dermatology teaching clinic at China Medical University Hospital from 30 December 2014 to 21 April 2015. Clinical diagnoses of 13 patients were made before and after using VCDDSS. Questionnaires were filled out at the end. The consultant dermatologist’s diagnosis was defined as the standard answer; the Sign test was used to analyse diagnostic accuracy and the Fisher exact test to analyse questionnaires.

Results

There was an 18.75% increase in diagnostic accuracy after use of VCDDSS (62.5–81.25%; p value <0.01). Significant associations were found in diagnostic assistance in terms of user factors such as accessibility, interface satisfaction, quality of imaging, textual description, and a Chinese language interface option (p value<0.01).

Conclusions

This study demonstrated that VCDDSS increases diagnostic accuracy by 18.75%, which means we can avoid possible misdiagnosis, provide better treatment, and avoid waste of medical resources. The user satisfaction is high. We expect wider application of this kind of decision support system in clinical practice, medical education, residency training, and patient education in the future. Further large-scale studies should be planned to confirm its application.
Targeting the SUMO pathway for neuroprotection in brain ischaemia
Authors: Yang Wei , Sheng Huaxin , Wang Haichen
Published: September 2016

Small ubiquitin-like modifier (SUMO) conjugation (SUMOylation) is a post-translational protein modification that modulates almost all major cellular processes, and has been implicated in many human diseases. A growing body of evidence from in vitro and in vivo studies demonstrates that increasing global levels of SUMO conjugated proteins (global SUMOylation) protects cells against ischaemia-induced damage, while suppressing global SUMOylation promotes cell injury after ischaemia. Indeed, SUMOylation has emerged as a potential therapeutic target for neuroprotection in brain ischaemia, including global brain ischaemia and focal brain ischaemia (ischaemic stroke). Here, we summarise findings on the role of SUMOylation in human diseases, brain ischaemia in particular, and review recent developments in drug discovery targeting SUMOylation with a major focus on its neuroprotective applications.
The role of cancer stem cells in tumor heterogeneity and resistance to therapy
Authors: Konrad Christina Valbirk , Murali Reshma , Varghese Binitha Anu , Nair Radhika
Published: September 2016

Cancer is a heterogenous disease displaying marked inter- and intra-tumoral diversity. The existence of cancer stem cells (CSCs) has been experimentally demonstrated in a number of cancer types as a subpopulation of tumor cells that drives the tumorigenic and metastatic properties of the entire cancer. Thus, eradication of the CSC population is critical for the complete ablation of a tumor. This is, however, confounded by the inherent resistance of CSCs to standard anticancer therapies, eventually leading to the outgrowth of resistant tumor cells and relapse in patients. The cellular mechanisms of therapy resistance in CSCs are ascribed to several factors including a state of quiescence, an enhanced DNA damage response and active repair mechanisms, up-regulated expression of drug efflux transporters, as well as the activation of pro-survival signaling pathways and inactivation of apoptotic signaling. Understanding the mechanisms underlying the acquisition of resistance to therapy may hold the key to targeting the CSC population.
Hafnium isotope constraints on the origin of Mesoarchaean andesites in southern West Greenland, North Atlantic Craton
Authors: Szilas Kristoffer , Tusch Jonas , Hoffmann J. Elis , Garde Adam A. , Münker Carsten
Published: September 2016

Numerous supracrustal belts in southern West Greenland host leucoamphibolites, which commonly preserve volcaniclastic textures, and are interpreted as meta-andesites. Such rocks are associated with mesocratic amphibolites of tholeiitic basaltic compositions, which display pillow-lava structures and, thus, support eruption in an oceanic environment. Here we present bulk-rock Lu–Hf isotope data for meta-andesites from the approximately 3071 Ma Qussuk supracrustal belt. Surprisingly, we find evidence for the involvement of a source with near-chondritic Hf-isotope composition in the meta-andesites, whereas the metabasalts display more depleted compositions, with

ε

Hf

3071

Ma

around +4. Trace element modelling indicates that fractional crystallization in combination with crustal assimilation (AFC) is not capable of producing the geochemical compositions of the meta-andesitic rocks from a basaltic melt. Instead, these meta-andesites point to large degrees (
c.
50%) of magma mixing, involving mafic and felsic end members. This may either represent: (1) a magma chamber process; (2) mantle-wedge overprinting by a silicic component; or (3) large degrees of melting of primitive mafic crust. Given that there is abundant independent structural and metamorphic evidence for horizontal tectonics in the Archaean crust of southern West Greenland, it is likely that these calc-alkaline meta-andesites and tholeiitic metabasalts were produced by Mesoarchaean subduction zone volcanism.
Pulmonary artery smooth muscle cell hyperproliferation and metabolic shift triggered by pulmonary overcirculation
Authors: Boehme Jason , Sun Xutong , Tormos Kathryn V. , Gong Wenhui , Kellner Manuela , Datar Sanjeev A. , Kameny Rebecca Johnson , Yuan Jason X.-J. , Raff Gary W. , Fineman Jeffrey R. , Black Stephen M. , Maltepe Emin
Published: September 2016

Vascular cell hyperproliferation and metabolic reprogramming contribute to the pathophysiology of pulmonary arterial hypertension (PAH). An important cause of PAH in children with congenital heart disease (CHD) is increased pulmonary blood flow (PBF). To better characterize this disease course we studied early changes in pulmonary artery smooth muscle cell (PASMC) proliferation and metabolism using a unique ovine model of pulmonary overcirculation. Consistent with PAH in adults, PASMCs derived from 4-wk-old lambs exposed to increased PBF (shunt) exhibited increased rates of proliferation. While shunt PASMCs also exhibited significant decreases in mitochondrial oxygen consumption, membrane potential, and tricarboxylic acid (TCA) cycle function, suggesting a switch to Warburg metabolism as observed in advanced PAH in adults, they unexpectedly demonstrated decreased glycolytic lactate production, likely due to enhanced flux through the pentose phosphate pathway (PPP). This may be a response to the marked increase in NADPH oxidase (Nox) activity and decreased NADPH/NADP+ratios observed in shunt PASMCs. Consistent with these findings, pharmacological inhibition of Nox activity preferentially slowed the growth of shunt PASMCs in vitro. Our results therefore indicate that PASMC hyperproliferation is observed early in the setting of pulmonary overcirculation and is accompanied by a unique metabolic profile that is independent of HIF-1α, PDHK1, or increased glycolytic flux. Our results also suggest that Nox inhibition may help prevent pulmonary overcirculation-induced PAH in children born with CHD.
Pathways for insulin access to the brain: the role of the microvascular endothelial cell
Authors: Meijer Rick I. , Gray Sarah M. , Aylor Kevin W. , Barrett Eugene J.
Published: September 2016

Insulin affects multiple important central nervous system (CNS) functions including memory and appetite, yet the pathway(s) by which insulin reaches brain interstitial fluid (bISF) has not been clarified. Recent studies demonstrate that to reach bISF, subarachnoid cerebrospinal fluid (CSF) courses through the Virchow-Robin space (VRS) which sheaths penetrating pial vessels down to the capillary level. Whether insulin predominantly enters the VRS and bISF by local transport through the blood-brain barrier, or by being secreted into the CSF by the choroid plexus, is unknown. We injected125I-TyrA14-insulin or regular insulin intravenously and compared the rates of insulin reaching subarachnoid CSF with its plasma clearance by brain tissue samples (an index of microvascular endothelial cell binding/uptake/transport). The latter process was more than 40-fold more rapid. We then showed that selective insulin receptor blockade or 4 wk of high-fat feeding each inhibited microvascular brain125I-TyrA14-insulin clearance. We further confirmed that125I-TyrA14-insulin was internalized by brain microvascular endothelial cells, indicating that the in vivo tissue association reflected cellular transport, not simply microvascular tracer binding.
Heart rate-induced modifications of concentric left ventricular hypertrophy: exploration of a novel therapeutic concept
Authors: Klein Franziska J. , Bell Stephen , Runte K. Elisabeth , Lobel Robert , Ashikaga Takamuru , Lerman Lilach O. , LeWinter Martin M. , Meyer Markus
Published: September 2016

Lowering the heart rate is considered to be beneficial in heart failure (HF) with reduced ejection fraction (HFrEF). In a dilated left ventricle (LV), pharmacological heart rate lowering is associated with a reduction in LV chamber size. In patients with HFrEF, this structural change is associated with better survival. HF with preserved ejection fraction (HFpEF) is increasingly prevalent but, so far, without any evidence-based treatment. HFpEF is typically associated with LV concentric remodeling and hypertrophy. The effects of heart rate on this structural phenotype are not known. Analogous with the benefits of a low heart rate on a dilated heart, we hypothesized that increased heart rates could lead to potentially beneficial remodeling of a concentrically hypertrophied LV. This was explored in an established porcine model of concentric LV hypertrophy and fibrosis. Our results suggest that a moderate increase in heart rate can be used to reduce wall thickness, normalize LV chamber volumes, decrease myocardial fibrosis, and improve LV compliance. Our results also indicate that the effects of heart rate can be titrated, are reversible, and do not induce HF. These findings may provide the rationale for a novel therapeutic approach for HFpEF and its antecedent disease substrate.

Listen to this article’s corresponding podcast at http://ajpheart.podbean.com/e/heart-rate-modeling/ .
How does pulmonary endarterectomy cure CTEPH: a clue to cure PAH?
Authors: Oka Masahiko , McMurtry Ivan F. , Oshima Kaori
Published: September 2016

Chronic thromboembolic pulmonary hypertension (CTEPH) is a hot topic in the field of pulmonary hypertension because many CTEPH patients are now curable by surgical pulmonary endarterectomy. However, there are still uncertainties regarding the pathogenesis of CTEPH, specifically how and where the small vessel arteriopathy that is indistinguishable from that in pulmonary arterial hypertension (plexogenic arteriopathy) develops and how pulmonary endarterectomy improves hemodynamics and possibly cures CTEPH. Based on our recent experimental finding that hemodynamic stress is fundamental for the development of plexogenic arteriopathy, we discuss the uncertainties of CTEPH and potential implication of the effectiveness of pulmonary endarterectomy for reversing plexogenic arteriopathy and possibly providing a novel approach to cure pulmonary arterial hypertension.
Update on novel targets and potential treatment avenues in pulmonary hypertension
Authors: Huetsch John C. , Suresh Karthik , Bernier Meghan , Shimoda Larissa A.
Published: September 2016

Pulmonary hypertension (PH) is a condition marked by a combination of constriction and remodeling within the pulmonary vasculature. It remains a disease without a cure, as current treatments were developed with a focus on vasodilatory properties but do not reverse the remodeling component. Numerous recent advances have been made in the understanding of cellular processes that drive pathologic remodeling in each layer of the vessel wall as well as the accompanying maladaptive changes in the right ventricle. In particular, the past few years have yielded much improved insight into the pathways that contribute to altered metabolism, mitochondrial function, and reactive oxygen species signaling and how these pathways promote the proproliferative, promigratory, and antiapoptotic phenotype of the vasculature during PH. Additionally, there have been significant advances in numerous other pathways linked to PH pathogenesis, such as sex hormones and perivascular inflammation. Novel insights into cellular pathology have suggested new avenues for the development of both biomarkers and therapies that will hopefully bring us closer to the elusive goal: a therapy leading to reversal of disease.
Comparative Analysis of Bispecific Antibody and Streptavidin-Targeted Radioimmunotherapy for B-cell Cancers
Authors: Green Damian J. , Frayo Shani L. , Lin Yukang , Hamlin Donald K. , Fisher Darrell R. , Frost Sofia H.L. , Kenoyer Aimee L. , Hylarides Mark D. , Gopal Ajay K. , Gooley Theodore A. , Orozco Johnnie J. , Till Brian G. , O'Steen Shyril , Orcutt Kelly D. , Wilbur D. Scott , Wittrup K. Dane , Press Oliver W.
Published: September 2016

Streptavidin (SA)-biotin pretargeted radioimmunotherapy (PRIT) that targets CD20 in non-Hodgkin lymphoma (NHL) exhibits remarkable efficacy in model systems, but SA immunogenicity and interference by endogenous biotin may complicate clinical translation of this approach. In this study, we engineered a bispecific fusion protein (FP) that evades the limitations imposed by this system. Briefly, one arm of the FP was an anti-human CD20 antibody (2H7), with the other arm of the FP an anti-chelated radiometal trap for a radiolabeled ligand (yttrium[Y]-DOTA) captured by a very high-affinity anti-Y-DOTA scFv antibody (C825). Head-to-head biodistribution experiments comparing SA-biotin and bispecific FP (2H7-Fc-C825) PRIT in murine subjects bearing human lymphoma xenografts demonstrated nearly identical tumor targeting by each modality at 24 hours. However, residual radioactivity in the blood and normal organs was consistently higher following administration of 1F5-SA compared with 2H7-Fc-C825. Consequently, tumor-to-normal tissue ratios of distribution were superior for 2H7-Fc-C825 (P < 0.0001). Therapy studies in subjects bearing either Ramos or Granta subcutaneous lymphomas demonstrated that 2H7-Fc-C825 PRIT is highly effective and significantly less myelosuppressive than 1F5-SA (P < 0.0001). All animals receiving optimal doses of 2H7-Fc-C825 followed by 90Y-DOTA were cured by 150 days, whereas the growth of tumors in control animals progressed rapidly with complete morbidity by 25 days. In addition to demonstrating reduced risk of immunogenicity and an absence of endogenous biotin interference, our findings offer a preclinical proof of concept for the preferred use of bispecific PRIT in future clinical trials, due to a slightly superior biodistribution profile, less myelosuppression, and superior efficacy. Cancer Res; 76(22); 6669–79. ©2016 AACR.
Synthetic Lethality in PTEN-Mutant Prostate Cancer Is Induced by Combinatorial PI3K/Akt and BCL-XL Inhibition
Authors: Ren Wenying , Joshi Raghav , Mathew Paul
Published: September 2016

The bone-conserved metastatic phenotype of prostate cancer is a prototype of nonrandom metastatic behavior. Adhesion of prostate cancer cells to fibronectin via the integrin α5 (ITGA5) has been proposed as a candidate bone marrow niche localization mechanism. We hypothesized that the mechanisms whereby ITGA5 regulates the adhesion-mediated survival of prostate cancer cells will define novel therapeutic approaches. ITGA5 shRNA reduced expression of BCL-2 family members and induced apoptosis in PC-3 cells. In these PTEN-mutant cells, pharmacologic inhibition of the PI3K signaling pathway in combination with ITGA5 knockdown enhanced apoptosis. Chemical parsing studies with BH3 mimetics indicated that PI3K/Akt inhibition in combination with BCL-XL–specific inhibition induces synergistic apoptosis specifically in PTEN-mutant prostate cancer cells, whereas single-agent PI3K/Akt inhibitors did not. Given the importance of PTEN loss in the progression of prostate and other cancers, synthetic lethality induced by combinatorial PI3K/Akt and BCL-XL inhibition represents a valuable therapeutic strategy.

Implications: Activation of the PI3K pathway through PTEN loss represents a major molecular pathway in the progression of prostate and other cancers. This study defines a synthetic lethal therapeutic combination with significant translational potential.

Overview: Synthetic lethality in PTEN-mutant prostate cancer cells with combined PI3K/Akt and BCL-XL inhibition. PTEN-mutant prostate cancer cells expressing ITGA5 bind to fibronectin in the putative bone marrow niche and transduce survival signals to BCL-XL. Additional PTEN-regulated signals independent of the PI3K/Akt pathway likely feed into the BCL-XL–regulated survival program to explain synthetic lethality observed with the combination.

Visual Overview: http://mcr.aacrjournals.org/content/early/2016/12/02/1541-7786.MCR-16-0202/F1.large.jpg. Mol Cancer Res; 14(12); 1176–81. ©2016 AACR.
Response to Programmed Cell Death-1 Blockade in a Murine Melanoma Syngeneic Model Requires Costimulation, CD4, and CD8 T Cells
Authors: Homet Moreno Blanca , Zaretsky Jesse M. , Garcia-Diaz Angel , Tsoi Jennifer , Parisi Giulia , Robert Lidia , Meeth Katrina , Ndoye Abibatou , Bosenberg Marcus , Weeraratna Ashani T. , Graeber Thomas G. , Comin-Anduix Begoña , Hu-Lieskovan Siwen , Ribas Antoni
Published: September 2016

The programmed cell death protein 1 (PD-1) limits effector T-cell functions in peripheral tissues, and its inhibition leads to clinical benefit in different cancers. To better understand how PD-1 blockade therapy modulates the tumor–host interactions, we evaluated three syngeneic murine tumor models, the BRAFV600E-driven YUMM1.1 and YUMM2.1 melanomas, and the carcinogen-induced murine colon adenocarcinoma MC38. The YUMM cell lines were established from mice with melanocyte-specific BRAFV600E mutation and PTEN loss (BRAFV600E/PTEN−/−). Anti–PD-1 or anti–PD-L1 therapy engendered strong antitumor activity against MC38 and YUMM2.1, but not YUMM1.1. PD-L1 expression did not differ between the three models at baseline or upon interferon stimulation. Whereas mutational load was high in MC38, it was lower in both YUMM models. In YUMM2.1, the antitumor activity of PD-1 blockade had a critical requirement for both CD4 and CD8 T cells, as well as CD28 and CD80/86 costimulation, with an increase in CD11c+CD11b+MHC-IIhigh dendritic cells and tumor-associated macrophages in the tumors after PD-1 blockade. Compared with YUMM1.1, YUMM2.1 exhibited a more inflammatory profile by RNA sequencing analysis, with an increase in expression of chemokine-trafficking genes that are related to immune cell recruitment and T-cell priming. In conclusion, response to PD-1 blockade therapy in tumor models requires CD4 and CD8 T cells and costimulation that is mediated by dendritic cells and macrophages. Cancer Immunol Res; 4(10); 845–57. ©2016 AACR.
Decoding the Long Noncoding RNA During Cardiac Maturation
Authors: Touma Marlin , Kang Xuedong , Zhao Yan , Cass Ashley A. , Gao Fuying , Biniwale Reshma , Coppola Giovanni , Xiao Xinshu , Reemtsen Brian , Wang Yibin
Published: September 2016

Background—

Cardiac maturation during perinatal transition of heart is critical for functional adaptation to hemodynamic load and nutrient environment. Perturbation in this process has major implications in congenital heart defects. Transcriptome programming during perinatal stages is an important information but incomplete in current literature, particularly, the expression profiles of the long noncoding RNAs (lncRNAs) are not fully elucidated.

Methods and Results—

From comprehensive analysis of transcriptomes derived from neonatal mouse heart left and right ventricles, a total of 45 167 unique transcripts were identified, including 21 916 known and 2033 novel lncRNAs. Among these lncRNAs, 196 exhibited significant dynamic regulation along maturation process. By implementing parallel weighted gene co-expression network analysis of mRNA and lncRNA data sets, several lncRNA modules coordinately expressed in a developmental manner similar to protein coding genes, while few lncRNAs revealed chamber-specific patterns. Out of 2262 lncRNAs located within 50 kb of protein coding genes, 5% significantly correlate with the expression of their neighboring genes. The impact of Ppp1r1b-lncRNA on the corresponding partner gene Tcap was validated in cultured myoblasts. This concordant regulation was also conserved in human infantile hearts. Furthermore, the Ppp1r1b-lncRNA/Tcap expression ratio was identified as a molecular signature that differentiated congenital heart defect phenotypes.

Conclusions—

The study provides the first high-resolution landscape on neonatal cardiac lncRNAs and reveals their potential interaction with mRNA transcriptome during cardiac maturation. Ppp1r1b-lncRNA was identified as a regulator of Tcap expression, with dynamic interaction in postnatal cardiac development and congenital heart defects.
Improved performance, within-individual consistency and between-individual differences in the righting behaviour of the Caribbean sea star, Oreaster reticulatus
Authors: Gutowsky Lee F.G. , Brownscombe Jacob W. , Wilson Alexander D.M. , Szekeres Petra , Cooke Steven J.
Published: September 2016

Individuals cope differently to challenging and stressful situations. Being inverted is challenging and stressful for animals, as the position leaves them vulnerable to predators and desiccation. Although sea star self-righting was first studied in the 19th century, efforts to quantify patterns of within-individual consistency and among-individual differences are limited. Here we examined the performance and repeatability of righting behaviour in the Caribbean sea star (Oreaster reticulatus).Oreaster reticulatuswere wild caught and transported to a nearby facility where they were inverted up to five times. Most animals improved their righting times and exhibited within-individual consistency and among individual differences in righting method. We posit that it may be favourable to employ a consistent righting method to effectively achieve an upright position. Predation pressure and stress physiology are hypothesized to shape individual differences in righting behaviour. Moreover, these results provide preliminary evidence of personality in sea stars.
Racial Capitalism and the Crisis of Black Masculinity
Authors: Matlon Jordanna
Published: September 2016

In this article, I theorize “complicit masculinity” to examine how access to capital, in other words, making or spending money, mediates masculine identity for un- and underemployed black men. Arguing that hegemony operates around producer-provider norms of masculinity and through tropes of blackness within a system of racial capitalism, I show how complicity underscores the reality of differential aspirational models in the context of severe un- and underemployment and the failure of the classic breadwinner model for black men globally. I draw on participant observation fieldwork and interviews with men from Abidjan, Côte d’Ivoire’s informal sector from 2008 to 2009. I investigate two groups of men: political propagandists (orators) for former President Laurent Gbagbo and mobile street vendors. Rejecting racialized colonial narratives that positioned salaried workers as “evolved,” orators used anti-French rhetoric and ties to the political regime to pursue entrepreneurial identities. Vendors, positioned as illegitimate workers and non-citizens, asserted consumerist models of masculinity from global black popular culture. I show how entrepreneurialism and consumerism, the two paradigmatic neoliberal identities, have become ways for black men to assert economic participation as alternatives to the producer-provider ideal.
Going Back in Time? Gender Differences in Trends and Sources of the Racial Pay Gap, 1970 to 2010
Authors: Mandel Hadas , Semyonov Moshe
Published: September 2016

Using IPUMS data for five decennial years between 1970 and 2010, we delineate and compare the trends and sources of the racial pay gap among men and women in the U.S. labor force. Decomposition of the pay gap into components underscores the significance of the intersection between gender and race; we find meaningful gender differences in the composition of the gap and in the gross and the net earnings gaps—both are much larger among men than among women. Despite these differences, the over-time trend is strikingly similar for both genders. Racial gaps sharply declined between 1970 and 1980 and continued to decline, but at a slower rate, until 2000. However, at the turn of the millennium, the trend reversed for both gender groups. The growth of the racial pay gap at the turn of the millennium is attributable to the increase in overall income inequality, stagnation in occupational segregation, and an increase in the unexplained portion of the gap, a portion we attribute to economic discrimination.
How Parents Fare
Authors: Musick Kelly , Meier Ann , Flood Sarah
Published: September 2016

The shift to more time-intensive and child-centered parenting in the United States is widely assumed to be positively linked to healthy child development, but implications for adult well-being are less clear. We assess multiple dimensions of parents’ subjective well-being in activities with children and explore how the gendered nature of time potentially contributes to differences in mothers’ and fathers’ parenting experiences. Relying on nationally representative time diary data linked to respondents’ feelings in activities from the 2010, 2012, and 2013 well-being module of the American Time Use Survey ( N = 12,163 persons and 36,036 activities), we find that parents consistently report greater subjective well-being in activities with children than without. Mothers, however, report less happiness, more stress, and greater fatigue in time with children than do fathers. These gaps are relatively small and can be accounted for by differences in the activities that mothers and fathers engage in with children, whether other adults are present, and the quality of their sleep and leisure. We go beyond prior work on parental happiness and life satisfaction to document how contemporary parenting is woven differently into the lives of mothers and fathers.
Whose Backyard and What’s at Issue? Spatial and Ideological Dynamics of Local Opposition to Fracking in New York State, 2010 to 2013
Authors: Dokshin Fedor A.
Published: September 2016

What drives local decisions to prohibit industrial land uses? This study examines the passage of municipal ordinances prohibiting gas development using hydraulic fracturing (“fracking”) in New York State. I argue that local action against fracking depended on multiple conceptions of the shale gas industry. Matching these alternative conceptions with prevailing spatial models of public response to industrial land uses—“not in my backyard,” “not in anyone’s backyard,” and “please in my backyard”—improves our understanding of where local contention might emerge and how it contributes to policy change. Results from event history and logistic regression analyses show, first, that communities lying above favorable areas of the shale did not pass anti-fracking laws because opposition to fracking was counteracted by significant local support for development. Fracking bans passed primarily in a geographic sweet spot on the periphery of targeted regions, where little or no compelling economic interest in development existed. Second, as fracking became the subject of a highly politicized national debate, local opposition increasingly reflected mobilization by political liberals. This trend is reflected in the increasing rate of ordinance adoption among Democratic-leaning communities outside the geographic sweet spot.
Package Design Affects Accuracy Recognition for Medications
Authors: Endestad Tor , Wortinger Laura A. , Madsen Steinar , Hortemo Sigurd
Published: September 2016

Objective:

Our aim was to test if highlighting and placement of substance name on medication package have the potential to reduce patient errors.

Background:

An unintentional overdose of medication is a large health issue that might be linked to medication package design. In two experiments, placement, background color, and the active ingredient of generic medication packages were manipulated according to best human factors guidelines to reduce causes of labeling-related patient errors.

Method:

In two experiments, we compared the original packaging with packages where we varied placement of the name, dose, and background of the active ingredient. Age-relevant differences and the effect of color on medication recognition error were tested. In Experiment 1, 59 volunteers (30 elderly and 29 young students), participated. In Experiment 2, 25 volunteers participated.

Results:

The most common error was the inability to identify that two different packages contained the same active ingredient (young, 41%, and elderly, 68%). This kind of error decreased with the redesigned packages (young, 8%, and elderly, 16%). Confusion errors related to color design were reduced by two thirds in the redesigned packages compared with original generic medications.

Conclusion:

Prominent placement of substance name and dose with a band of high-contrast color support recognition of the active substance in medications.

Application:

A simple modification including highlighting and placing the name of the active ingredient in the upper right-hand corner of the package helps users realize that two different packages can contain the same active substance, thus reducing the risk of inadvertent medication overdose.
Implementing Lumberjacks and Black Swans Into Model-Based Tools to Support Human–Automation Interaction
Authors: Sebok Angelia , Wickens Christopher D.
Published: September 2016

Objective:

The objectives were to (a) implement theoretical perspectives regarding human–automation interaction (HAI) into model-based tools to assist designers in developing systems that support effective performance and (b) conduct validations to assess the ability of the models to predict operator performance.

Background:

Two key concepts in HAI, the lumberjack analogy and black swan events, have been studied extensively. The lumberjack analogy describes the effects of imperfect automation on operator performance. In routine operations, an increased degree of automation supports performance, but in failure conditions, increased automation results in more significantly impaired performance. Black swans are the rare and unexpected failures of imperfect automation.

Method:

The lumberjack analogy and black swan concepts have been implemented into three model-based tools that predict operator performance in different systems. These tools include a flight management system, a remotely controlled robotic arm, and an environmental process control system.

Results:

Each modeling effort included a corresponding validation. In one validation, the software tool was used to compare three flight management system designs, which were ranked in the same order as predicted by subject matter experts. The second validation compared model-predicted operator complacency with empirical performance in the same conditions. The third validation compared model-predicted and empirically determined time to detect and repair faults in four automation conditions.

Conclusion:

The three model-based tools offer useful ways to predict operator performance in complex systems.

Application:

The three tools offer ways to predict the effects of different automation designs on operator performance.