bluuebunny/crossref_metadata_2025 huggingface dataset:
Response to Anti-EGFR Therapy in Patients with BRAF non-V600–Mutant Metastatic Colorectal Cancer
Authors: Yaeger Rona , Kotani Daisuke , Mondaca Sebastián , Parikh Aparna R. , Bando Hideaki , Van Seventer Emily E. , Taniguchi Hiroya , Zhao HuiYong , Thant Claire N. , de Stanchina Elisa , Rosen Neal , Corcoran Ryan B. , Yoshino Takayuki , Yao Zhan , Ebi Hiromichi
Published: September 2019

Purpose:

While mutations in BRAF in metastatic colorectal cancer (mCRC) most commonly occur at the V600 amino acid, with the advent of next-generation sequencing, non-V600 BRAF mutations are increasingly identified in clinical practice. It is unclear whether these mutants, like BRAF V600E, confer resistance to anti-EGFR therapy.

Experimental Design:

We conducted a multicenter pooled analysis of consecutive patients with non-V600 BRAF-mutated mCRCs identified between 2010 and 2017. Non-V600 BRAF mutations were divided into functional classes based on signaling mechanism and kinase activity: activating and RAS-independent (class 2) or kinase-impaired and RAS-dependent (class 3).

Results:

Forty patients with oncogenic non-V600 BRAF–mutant mCRC received anti-EGFR antibody treatment [n = 12 (30%) class 2 and n = 28 (70%) class 3]. No significant differences in clinical characteristics were observed by mutation class. In contrast, while only 1 of 12 patients with class 2 BRAF mCRC responded, 14 of 28 patients with class 3 BRAF responded to anti-EGFR therapy (response rate, 8% and 50%, respectively, P = 0.02). Specifically, in first- or second-line, 1 of 6 (17%) patients with class 2 and 7 of 9 (78%) patients with class 3 BRAF mutants responded (P = 0.04). In third- or later-line, none of 6 patients with class 2 and 7 of 19 (37%) patients with class 3 BRAF mutants responded (P = 0.14).

Conclusions:

Response to EGFR antibody treatment in mCRCs with class 2 BRAF mutants is rare, while a large portion of CRCs with class 3 BRAF mutants respond. Patients with colorectal cancer with class 3 BRAF mutations should be considered for anti-EGFR antibody treatment.

See related commentary by Fontana and Valeri, p. 6896
Model Informed Drug Development: Novel Oncology Agents are Lost in Translation
Authors: Mayawala Kapil , de Alwis Dinesh P. , Sachs Jeffrey R.
Published: September 2019

Excitement around and investment in oncology drug development are at unprecedented levels. To maximize the health impact and productivity of this research and development investment, quantitative modeling should impact key decisions in early clinical oncology including Go/No-Go decisions based on early clinical data, and dose selection for late stage studies.

See related article by Bottino et al., p. 6633
Ovarian Primary and Metastatic Tumors Suppressed by Survivin Knockout or a Novel Survivin Inhibitor
Authors: Zhao Guannan , Wang Qinghui , Wu Zhongzhi , Tian Xinchun , Yan Huan , Wang Baojin , Dong Peixin , Watari Hidemichi , Pfeffer Lawrence M. , Guo Yuqi , Li Wei , Yue Junming
Published: September 2019

Survivin, a member of the inhibitor of apoptosis family, is upregulated in multiple cancers including ovarian cancer, but is rarely detectable in normal tissues. We previously reported that survivin promoted epithelial-to-mesenchymal transition (EMT) in ovarian cancer cells, suggesting that survivin may contribute to ovarian tumor metastasis and chemoresistance. In this study, we tested whether knockout or pharmacologic inhibition of survivin overcomes chemoresistance and suppresses tumor metastasis. The genetic loss of survivin suppressed tumor metastasis in an orthotopic ovarian cancer mouse model. To pharmacologically test the role of survivin on ovarian tumor metastasis, we treated chemo-resistant ovarian cancer cells with a selective survivin inhibitor, MX106, and found that MX106 effectively overcame chemoresistance in vitro. MX106 inhibited cell migration and invasion by attenuating the TGFβ pathway and inhibiting EMT in ovarian cancer cells. To evaluate the efficacy of MX106 in inhibiting ovarian tumor metastasis, we treated an orthotopic ovarian cancer mouse model with MX106, and found that MX106 efficiently inhibited primary tumor growth in ovaries and metastasis in multiple peritoneal organs as compared with vehicle-treated control mice. Our data demonstrate that inhibition of survivin using either genetic knockout or a novel inhibitor MX106 suppresses primary ovarian tumor growth and metastasis, supporting that targeting survivin could be an effective therapeutic approach in ovarian cancer.
Machine-Learning Prediction of Tumor Antigen Immunogenicity in the Selection of Therapeutic Epitopes
Authors: Smith Christof C. , Chai Shengjie , Washington Amber R. , Lee Samuel J. , Landoni Elisa , Field Kevin , Garness Jason , Bixby Lisa M. , Selitsky Sara R. , Parker Joel S. , Savoldo Barbara , Serody Jonathan S. , Vincent Benjamin G.
Published: September 2019

Current tumor neoantigen calling algorithms primarily rely on epitope/major histocompatibility complex (MHC) binding affinity predictions to rank and select for potential epitope targets. These algorithms do not predict for epitope immunogenicity using approaches modeled from tumor-specific antigen data. Here, we describe peptide-intrinsic biochemical features associated with neoantigen and minor histocompatibility mismatch antigen immunogenicity and present a gradient boosting algorithm for predicting tumor antigen immunogenicity. This algorithm was validated in two murine tumor models and demonstrated the capacity to select for therapeutically active antigens. Immune correlates of neoantigen immunogenicity were studied in a pan-cancer data set from The Cancer Genome Atlas and demonstrated an association between expression of immunogenic neoantigens and immunity in colon and lung adenocarcinomas. Lastly, we present evidence for expression of an out-of-frame neoantigen that was capable of driving antitumor cytotoxic T-cell responses. With the growing clinical importance of tumor vaccine therapies, our approach may allow for better selection of therapeutically relevant tumor-specific antigens, including nonclassic out-of-frame antigens capable of driving antitumor immunity.
Renal Function Affects Prognostic Role of Antiphosphatidylserine Antibodies for Acute Ischemic Stroke Patients
Authors: Wang Guangli , Zhong Chongke , Peng Hao , Bu Xiaoqing , Wang Aili , Xu Tian , Peng Yanbo , Xu Tan , Li Qunwei , Ju Zhong , Geng Deqin , Chen Jing , Zhang Yonghong , He Jiang
Published: September 2019

Background: Whether the renal function influences the association between antiphosphatidylserine antibodies (aPS) and prognosis of ischemic stroke remains unclear. We aimed to investigate the prognostic value of aPS after ischemic stroke stratified by renal function status. Methods: This prospective study was based on China Antihypertensive Trial in Acute Ischemic Stroke, a randomized clinical trial in 26 hospitals across China from August 2009 to May 2013. A total of 2,874 ischemic stroke patients with blood samples or baseline records of estimated glomerular filtration rate (eGFR) were included in this study. Serum aPS levels were quantitatively measured at baseline, and abnormal renal function in this study was defined as eGFR <90 mL/min per 1.73 m2. The primary outcome was a combination of death and major disability (modified Rankin Scale score ≥3) at 3 months after stroke. Secondary outcomes were death and major disability separately. Results: The association between aPS and primary outcome was significantly modified by renal function status (p for interaction = 0.02). After adjustment for covariates, increased aPS were significantly associated with the primary outcome in the patients with abnormal renal function (OR 2.09; 95% CI 1.24–3.53; p for trend = 0.006), but not in those with normal renal function (OR 0.92; 95% CI 0.69–1.23; p for trend = 0.59), when 2 extreme tertiles were compared. Furthermore, multiple-adjusted spline regression model showed a linear association between aPS and risk of primary outcome in the patients with abnormal renal function (p for linearity = 0.02) but not in those with normal renal function (p for linearity = 0.71). Conclusions: Increased aPS were positively and independently associated with death or major disability after acute ischemic stroke in the patients with abnormal renal function.
Impact of Baseline Characteristics on the Overall Survival of HCC Patients Treated with Sorafenib: Ten Years of Experience
Authors: Rovesti Giulia , Orsi Giulia , Kalliopi Andrikou , Vivaldi Caterina , Marisi Giorgia , Faloppi Luca , Foschi Francesco Giuseppe , Silvestris Nicola , Pecora Irene , Aprile Giuseppe , Molinaro Eleonora , Riggi Laura , Ulivi Paola , Canale Matteo , Cucchetti Alessandro , Tamburini Emiliano , Ercolani Giorgio , Fornaro Lorenzo , Andreone Pietro , Zavattari Patrizia , Scartozzi Mario , Cascinu Stefano , Casadei-Gardini Andrea
Published: September 2019

Background: Sorafenib has been established as the standard of care for patients with advanced hepatocellular carcinoma (HCC) since 2007 on the basis of two landmark trials (SHARP and Asia-Pacific). Ten years have passed since then and, despite much research in the field, still no validated real-life prognostic markers are available for HCC patients treated with this drug. Therefore, going through 10 years of research into sorafenib of several Italian Cancer Centers, we conducted a field-practice study aimed at identifying baseline clinical factors that could be significantly associated with overall survival (OS). Method: Univariate/multivariate analyses were conducted to retrospectively identify the impact of baseline characteristics on the OS of 398 advanced HCC patients treated with sorafenib. Results: Based on univariate analysis, α-fetoprotein (AFP), albumin, AST, bilirubin, Child-Pugh, ECOG, systemic immune-inflammation index (SII), albumin-bilirubin (ALBI) grade, and portal vein thrombosis were significantly associated with shorter OS. Following adjustment for clinical covariates positive in univariate analysis, the multivariate analysis including AFP, age, etiology, albumin, aspartate transaminase (AST), bilirubin, Child-Pugh, LDH, platelet-to-lymphocyte ratio, ECOG, ALBI grade, portal vein thrombosis, SII, and BCLC stage identified increase in LDH, age >70 years, no viral etiologies, ECOG >0, albumin <35, ALBI grade 2, and AST >40 as prognostic factors for poorer OS based on the 5% significance level. Conclusion: Our study highlights that baseline hepatic function, patient-centered variables, and etiology have prognostic value. These findings might have implications in terms of therapeutic decision-making and patient counseling.
Cytoreductive Nephrectomy for Metastatic Renal Cell Carcinoma: How to Apply New Evidence in Clinical Practice
Authors: Soares Andrey , Maia Manuel C. , Vidigal Fernando , Marques Monteiro Fernando Sabino
Published: September 2019

Cytoreductive nephrectomy (CN) followed by systemic therapy had been considered the standard of care for metastatic renal cell carcinoma (mRCC) patients since two clinical trials established its role during the cytokines era. With introduction of new and effective drugs, such as vascular endothelial growth factor-targeted therapies, the role of CN started to be challenged. Retrospective studies conducted during the targeted therapy era pointed to better outcomes when CN was associated with systemic treatment, although certain patients with poor risk features did not seem to benefit. Therefore, prospective clinical trials supporting CN were needed. Recently, with the publication of two randomized trials evaluating CN in the targeted therapy era, it has been made clear that patient selection and multidisciplinary discussion are of paramount importance in order to achieve the best outcomes. We reviewed the available literature on the role of CN among mRCC patients, commenting on how to apply the new evidence into clinical practice and providing future perspectives.
IgG4-Related Disease with Esophageal Involvement
Authors: Jang Sung Wook , Jeon Min Ho , Shin Hyun Deok
Published: September 2019

We report the case of a 56-year-old man who presented with dysphagia and weight loss. An esophagoduodenoscopy revealed a severe esophageal stricture in the distal esophagus. After surgical resection, the final pathologic analysis revealed that the tumor was comprised of benign-appearing fibroinflammatory cells with an increase and predominance of IgG4-positive plasma cells. He did not, however, have any other symptoms indicative of systemic autoimmune disease or connective tissue disorders. Histologically, abundant infiltration of IgG4-positive plasma cells and lymphocytes was observed. The patient was diagnosed with IgG4-related disease, definitive, with esophageal involvement.
A Term Newborn with Lung Collapse since Birth
Authors: Aljassim Fatma , Elmelhat Ahmed Mohamed
Published: September 2019

Respiratory distress in a term newborn has a wide range of differential diagnoses. Lobar lung collapse as a cause of respiratory distress in a term newborn always raises the suspicion of congenital pneumonia but it is challenging to determine if (1) it presents since birth, (2) it has a migratory nature, and (3) infection was excluded as a cause. We report a case of lobar lung collapse in a full-term baby and present our management of the case until the underlying diagnosis was reached.
Sumário
Authors: Carvalho Lauro Fabiano Souza
Published: September 2019

Sumário do número
Elevated Plasma Ceramides Are Associated With Higher White Matter Hyperintensity Volume—Brief Report
Authors: Mielke Michelle M. , Syrjanen Jeremy A. , Bui Hai H. , Petersen Ronald C. , Knopman David S. , Jack Clifford R. , Graff-Radford Jonathan , Vemuri Prashanthi
Published: September 2019

Objective:

Sphingolipids, including S1P (sphingosine-1-phosphate) and ceramides, have been associated with vascular tone, blood pressure regulation, cardiovascular outcomes, and mortality. However, the relationship between plasma sphingolipids and cerebrovascular disease has not been examined. We aimed to assess the cross-sectional association between plasma sphingolipids and white matter hyperintensity (WMH) volume, which is a marker of cerebrovascular disease.

Approach and Results:

We included 588 participants (302 men and 286 women), aged 60 to 93, enrolled in the population-based Mayo Clinic Study of Aging who had MRI and plasma sphingolipids at the same study visit. Fasting plasma was obtained, and ceramides and S1P were assayed using liquid chromatography-electrospray ionization tandem mass spectrometry. Fluid-attenuated inversion recovery was used to measure WMH volume, defined as percent total intracranial volume. We used linear regression to cross-sectionally examine the relationships between plasma sphingolipids and WMH; both were log-transformed. In multivariable analyses adjusting for age, sex, and hypertension, higher levels of ceramide C16:0 (b [95% CI]=0.24 [0.02–0.45]) and the ceramide ratios C16:0_24:0 (b [95% CI]=0.30 [0.12–0.48]) and C24:1_24:0 (b [95% CI]=0.24 [0.07–0.41]) were associated with a higher WMH volume. A higher ceramide score was also associated with higher WMH volume (b [95% CI]=0.03 (0.01–0.04]). We did not observe any association between S1P and WMH volume.

Conclusions:

Higher plasma ceramide C16:0 and 2 specific ceramide ratios (C16:0_24:0 and C24:1_24:0) are associated with greater WMH volumes, independent of hypertension, suggesting their utility for measurement of cerebrovascular disease.
Treatments and Mortality Trends in Cases With and Without Dialysis Who Have an Acute Myocardial Infarction
Authors: Szummer Karolina , Lindhagen Lars , Evans Marie , Spaak Jonas , Koul Sasha , Åkerblom Axel , Carrero Juan Jesus , Jernberg Tomas
Published: September 2019

Background:

Patients on dialysis who have an acute myocardial infarction (AMI) have an exceedingly poor prognosis, but it is unknown to what extent guideline-recommended interventions and treatments are used and to which benefit. We aimed to assess temporal changes in the use of treatments and survival rates in dialysis patients with an AMI.

Methods and Results:

All consecutive AMI cases from 1996 to 2013 enrolled in the SWEDEHEART registry (Swedish Web–System for Enhancement and Development of Evidence-Based Care in Heart Disease Evaluated According to Recommended Therapies) were included. The Swedish Renal Registry identified all chronic dialysis cases. Multivariable adjusted standardized 1-year mortality was estimated. An age-sex-calendar year–matched dialysis background population from the Swedish Renal Registry was used to obtain a standardized incidence ratio. All analyses were performed in 2-year blocks, where each individual could be included several times but in different time blocks; hence the term AMI cases and not patients is used. Of 289 699 cases with AMI, 1398 (0.5%) were on dialysis (73.6% hemodialysis; 26.4% peritoneal dialysis). Among dialysis cases, 29.4% were women, and 21.0% had ST-segment–elevation myocardial infarction. Through 1996 to 2013, dialysis cases had similar age (median, 70 years [interquartile range, 62–77];
P
for trend, 0.14), but the proportion with diabetes mellitus increased (36.0%–55.3%;
P
for trend, 0.005). Dialysis cases admitted with AMI were treated more invasively and received more discharge medications in the later years. From 1995 to 2013, in-hospital and 1-year mortality decreased from 25.4% to 9.4% and from 59.6% to 41.2%, respectively. The standardized in-hospital and 1-year mortality decreased from 25.7% to 9.4% and from 54.6% to 41.2%. Yet, compared with the matched dialysis population, the odds of death remained as high in 2012/2013 as in 1996/1997 (odds ratio, 2.04; 95% CI, 1.62–2.58 and odds ratio, 1.99; 95% CI, 1.52–2.60, respectively;
P
for trend, 0.34).

Conclusions:

Over the last 18 years, more patients on dialysis with AMI have been treated with evidence-based therapies. Overall, dialysis cases with AMI have an improved in-hospital and 1-year survival in the more recent years compared with earlier years. However, this appears largely to be because of improved survival in the general dialysis population.
Cell-Specific Gene Deletion Reveals the Antithrombotic Function of COX1 and Explains the Vascular COX1/Prostacyclin Paradox
Authors: Mitchell Jane A. , Shala Fisnik , Elghazouli Youssef , Warner Timothy D. , Gaston-Massuet Carles , Crescente Marilena , Armstrong Paul C. , Herschman Harvey R. , Kirkby Nicholas S.
Published: September 2019

Rationale:

Endothelial cells (ECs) and platelets, which respectively produce antithrombotic prostacyclin and prothrombotic thromboxane A
2
, both express COX1 (cyclooxygenase1). Consequently, there has been no way to delineate any antithrombotic role for COX1-derived prostacyclin from the prothrombotic effects of platelet COX1. By contrast, an antithrombotic role for COX2, which is absent in platelets, is straightforward to demonstrate. This has resulted in an incomplete understanding of the relative importance of COX1 versus COX2 in prostacyclin production and antithrombotic protection in vivo.

Objective:

We sought to identify the role, if any, of COX1-derived prostacyclin in antithrombotic protection in vivo and compare this to the established protective role of COX2.

Methods and Results:

We developed vascular-specific COX1 knockout mice and studied them alongside endothelial-specific COX2 knockout mice. COX1 immunoreactivity and prostacyclin production were primarily associated with the endothelial layer of aortae; freshly isolated aortic ECs released >10-fold more prostacyclin than smooth muscle cells. Moreover, aortic prostacyclin production, the ability of aortic rings to inhibit platelet aggregation and plasma prostacyclin levels were reduced when COX1 was knocked out in ECs but not in smooth muscle cells. When thrombosis was measured in vivo after FeCl
3
carotid artery injury, endothelial COX1 deletion accelerated thrombosis to a similar extent as prostacyclin receptor blockade. However, this effect was lost when COX1 was deleted from both ECs and platelets. Deletion of COX2 from ECs also resulted in a prothrombotic phenotype that was independent of local vascular prostacyclin production.

Conclusions:

These data demonstrate for the first time that, in healthy animals, endothelial COX1 provides an essential antithrombotic tone, which is masked when COX1 activity is lost in both ECs and platelets. These results help us define a new 2-component paradigm wherein thrombotic tone is regulated by both COX1 and COX2 through complementary but mechanistically distinct pathways.
Bleeding and New Cancer Diagnosis in Patients With Atherosclerosis
Authors: Eikelboom John W. , Connolly Stuart J. , Bosch Jacqueline , Shestakovska Olga , Aboyans Victor , Alings Marco , Anand Sonia S. , Avezum Alvaro , Berkowitz Scott D. , Bhatt Deepak L. , Cook-Bruns Nancy , Felix Camilo , Fox Keith A.A. , Hart Robert G. , Maggioni Aldo P. , Moayyedi Paul , O’Donnell Martin , Rydén Lars , Verhamme Peter , Widimsky Petr , Zhu Jun , Yusuf Salim ,   On behalf of the COMPASS Investigators
Published: September 2019

Background:

Patients treated with antithrombotic drugs are at risk of bleeding. Bleeding may be the first manifestation of underlying cancer.

Methods:

We examined new cancers diagnosed in relation to gastrointestinal or genitourinary bleeding among patients enrolled in the COMPASS trial (Cardiovascular Outcomes for People Using Anticoagulation Strategies) and determined the hazard of new cancer diagnosis after bleeding at these sites.

Results:

Of 27 395 patients enrolled (mean age, 68 years; women, 21%), 2678 (9.8%) experienced any (major or minor) bleeding, 713 (2.6%) experienced major bleeding, and 1084 (4.0%) were diagnosed with cancer during a mean follow-up of 23 months. Among 2678 who experienced bleeding, 257 (9.9%) were subsequently diagnosed with cancer. Gastrointestinal bleeding was associated with a 20-fold higher hazard of new gastrointestinal cancer diagnosis (7.4% versus 0.5%; hazard ratio [HR], 20.6 [95% CI, 15.2–27.8]) and 1.7-fold higher hazard of new nongastrointestinal cancer diagnosis (3.8% versus 3.1%; HR, 1.70 [95% CI, 1.20–2.40]). Genitourinary bleeding was associated with a 32-fold higher hazard of new genitourinary cancer diagnosis (15.8% versus 0.8%; HR, 32.5 [95% CI, 24.7–42.9]), and urinary bleeding was associated with a 98-fold higher hazard of new urinary cancer diagnosis (14.2% versus 0.2%; HR, 98.5; 95% CI, 68.0–142.7). Nongastrointestinal, nongenitourinary bleeding was associated with a 3-fold higher hazard of nongastrointestinal, nongenitourinary cancers (4.4% versus 1.9%; HR, 3.02 [95% CI, 2.32–3.91]).

Conclusions:

In patients with atherosclerosis treated with antithrombotic drugs, any gastrointestinal or genitourinary bleeding was associated with higher rates of new cancer diagnosis. Any gastrointestinal or genitourinary bleeding should prompt investigation for cancers at these sites.

Clinical Trial Registration:

URL:
https://www.clinicaltrials.gov
. Unique identifier: NCT01776424.
Impact of a Multidisciplinary Treatment Pathway for Atrial Fibrillation in the Emergency Department on Hospital Admissions and Length of Stay: Results of a Multi‐Center Study
Authors: Ptaszek Leon M. , Baugh Christopher W. , Lubitz Steven A. , Ruskin Jeremy N. , Ha Grace , Forsch Margaux , DeOliveira Samer A. , Baig Samia , Heist E. Kevin , Wasfy Jason H. , Brown David F. , Biddinger Paul D. , Raja Ali S. , Scirica Benjamin , White Benjamin A. , Mansour Moussa
Published: September 2019

Background

Variability in the management of atrial fibrillation (
AF
) in the emergency department (
ED
) leads to avoidable hospital admissions and prolonged length of stay (
LOS
). In a retrospective single‐center study, a multidisciplinary
AF
treatment pathway was associated with a reduced hospital admission rate and reduced
LOS
. To assess the applicability of the
AF
pathway across institutions, we conducted a 2‐center study.

Methods and Results

We performed a prospective, 2‐stage study at 2 tertiary care hospitals. During the first stage,
AF
patients in the
ED
received routine care. During the second stage,
AF
patients received care according to the
AF
pathway. The primary study outcome was hospital admission rate. Secondary outcomes included
ED LOS
and inpatient
LOS
. We enrolled 104 consecutive patients in each stage. Patients treated using the
AF
pathway were admitted to the hospital less frequently than patients who received routine care (15% versus 55%;
P
<0.001). For admitted patients, average hospital
LOS
was shorter in the
AF
pathway cohort than in the routine care cohort (64 versus 105 hours, respectively;
P
=0.01). There was no significant difference in the average
ED LOS
between
AF
pathway and routine care cohorts (14 versus 12 hours, respectively;
P
=0.32).

Conclusions

In this prospective 2‐stage, 2‐center study, utilization of a multidisciplinary
AF
treatment pathway resulted in a 3.7‐fold reduction in admission rate and a 1.6‐fold reduction in average hospital
LOS
for admitted patients. Utilization of the
AF
pathway was not associated with a significant change in
ED LOS
.
Renal Resistive Index Is Associated With Inactive Matrix Gla (γ‐Carboxyglutamate) Protein in an Adult Population‐Based Study
Authors: Jaques David A. , Pivin Edward , Pruijm Menno , Ackermann Daniel , Guessous Idris , Ehret Georg , Wei Fang‐Fei , Staessen Jan A. , Pechère‐Bertschi Antoinette , Vermeer Cees , Vogt Bruno , Burnier Michel , Martin Pierre‐Yves , Bochud Murielle , Ponte Belen
Published: September 2019

Background

Increased renal resistive index (
RRI
) has been associated with target organ damage as well as renal and cardiovascular outcomes. Matrix Gla (γ‐carboxyglutamate) protein (
MGP
) is a strong inhibitor of soft tissue calcification. Its inactive form (dephospho‐uncarboxylated MGP [dp‐uc
MGP
]) has been associated with vascular stiffness, cardiovascular outcomes, and mortality. In this study, we hypothesized that high levels of dp‐uc
MGP
were associated with increased
RRI
.

Methods and Results

We recruited participants via a multicenter family‐based cross‐sectional study in Switzerland. Levels of dp‐uc
MGP
were measured in plasma by sandwich
ELISA
.
RRI
was measured by Doppler ultrasound in 3 segmental arteries in both kidneys. We used mixed regression models to assess the relationship between dp‐uc
MGP
and
RRI
. We adjusted for common determinants of
RRI
as well as renal function and cardiovascular risk factors. We included 1006 participants in our analyses: 526 women and 480 men. Mean values were 0.44±0.20 nmol/L for dp‐uc
MGP
and 64±5% for
RRI
. After multivariable adjustment, dp‐uc
MGP
was positively associated with
RRI
(
P
=0.001). In subgroup analysis by age tertiles, this association was not significant in the youngest age group (<38 years;
P
=0.62), whereas it was significant in older age groups (38–55 and >55 years;
P
=0.016 and
P
<0.001, respectively).

Conclusions

Levels of dp‐uc
MGP
are positively and independently associated with
RRI
after adjustment for common determinants of
RRI
, cardiovascular risk factors, and renal function. The stronger association among older adults is probably due, in part, to age‐related arterial stiffness.
RRI
thus seems to reflect the global atherosclerotic burden in a general adult population.
Brain Connectivity Measures Improve Modeling of Functional Outcome After Acute Ischemic Stroke
Authors: Ktena Sofia Ira , Schirmer Markus D. , Etherton Mark R. , Giese Anne-Katrin , Tuozzo Carissa , Mills Brittany B. , Rueckert Daniel , Wu Ona , Rost Natalia S.
Published: September 2019

Background and Purpose—

The ability to model long-term functional outcomes after acute ischemic stroke represents a major clinical challenge. One approach to potentially improve prediction modeling involves the analysis of connectomics. The field of connectomics represents the brain’s connectivity as a graph, whose topological properties have helped uncover underlying mechanisms of brain function in health and disease. Specifically, we assessed the impact of stroke lesions on rich club organization, a high capacity backbone system of brain function.

Methods—

In a hospital-based cohort of 41 acute ischemic stroke patients, we investigated the effect of acute infarcts on the brain’s prestroke rich club backbone and poststroke functional connectomes with respect to poststroke outcome. Functional connectomes were created using 3 anatomic atlases, and characteristic path-length (
L
) was calculated for each connectome. The number of rich club regions affected were manually determined using each patient’s diffusion weighted image. We investigated differences in
L
with respect to outcome (modified Rankin Scale score; 90 days) and the National Institutes of Health Stroke Scale (NIHSS; early: 2–5 days; late: 90-day follow-up). Furthermore, we assessed the effect of including number of rich club regions and
L
in outcome models, using linear regression and assessing the explained variance (R
2
).

Results—

Of 41 patients (mean age [range]: 70 [45–89] years), 61% were male. Lower
L
was generally associated with better outcome. Including number of rich club regions in the backward selection models of outcome, R
2
increased between 1.3- and 2.6-fold beyond that of traditional markers (age and acute lesion volume) for NIHSS and modified Rankin Scale score.

Conclusions—

In this proof-of-concept study, we showed that information on network topology can be leveraged to improve modeling of poststroke functional outcome. Future studies are warranted to validate this approach in larger prospective studies of outcome prediction in stroke.
Clot-Derived Contaminants in Transplanted Bone Marrow Mononuclear Cells Impair the Therapeutic Effect in Stroke
Authors: Okinaka Yuka , Kikuchi-Taura Akie , Takeuchi Yukiko , Ogawa Yuko , Boltze Johannes , Gul Sheraz , Claussen Carsten , Taguchi Akihiko
Published: September 2019

Background and Purpose—

The beneficial effects of bone marrow mononuclear cell (BM-MNC) transplantation in preclinical experimental stroke have been reliably demonstrated. However, only overall modest effects in clinical trials were observed. We have investigated and reported a cause of the discrepancy between the preclinical and clinical studies.

Methods—

To investigate the possible cause of low efficacy of BM-MNC transplantation in experimental stroke, we have focused on blood clot formation, which is not uncommon in human bone marrow aspirates. To evaluate the effects of clot-derived contaminants in transplanted BM-MNC on stroke outcome, a murine stroke model was used.

Results—

We show that BM-MNC separated by an automatic cell isolator (Sepax2), which does not have the ability to remove clots, did not attenuate brain atrophy after stroke. In contrast, manually isolated, clot-free BM-MNC exerted therapeutic effects. Clot-derived contaminants were also transplanted intravenously to poststroke mice. We found that the transplanted contaminants were trapped at the peristroke area, which were associated with microglial/macrophage activation.

Conclusions—

Clot-derived contaminants in transplanted BM-MNC nullify therapeutic effects in experimental stroke. This may explain neutral results in clinical trials, especially in those using automated stem cell separators that lack the ability to remove clot-derived contaminants.

Visual Overview—

An online
visual overview
is available for this article.
The Politics of Free, Prior and Informed Consent: Indigenous Rights and Resource Governance in Ecuador and Yukon, Canada
Authors: Rice Roberta
Published: September 2019

What are the institutional arrangements required to implement a genuine process of free, prior and informed consent (fpic)? This article provides a comparative perspective on the politics of consent in the context of relations between Indigenous peoples, states and extractive industries in Canada and Latin America. The case of Ecuador is presented as an emblematic example of a hybrid regime in which Indigenous communities have the right to free, prior and informed consultation, not consent, concerning planned measures affecting them, such as mineral, oil and gas exploitation. In the case of Yukon, Canada, the settlement of a comprehensive land claim with sub-surface mineral rights has provided the institutional basis for the implementation of a genuine fpic process, one that includes participatory decision-making power over natural resource development projects. The article concludes with a discussion on the necessary conditions for moving governments from a consultation to a consent regime.
Mobilising Free, Prior and Informed Consent (fpic) from Below: A Typology of Indigenous Peoples’ Agency
Authors: Schilling-Vacaflor Almut , Flemmer Riccarda
Published: September 2019

Based on rich empirical data from Bolivia, Colombia, and Peru – the three Latin American countries where the implementation of prior consultation processes is most advanced – we present a typology of indigenous peoples’ agency surrounding prior consultation processes and the principle of free, prior and informed consent (fpic). The typology distinguishes between indigenous actors (1) mobilising for a strong legal interpretation of fpic, (2) mobilising for meaningful and influential fpic processes, (3) mobilising against prior consultation processes, and (4) blockading prior consultation processes for discussing broader grievances. We identify the most prominent indigenous strategies related to those four types, based on emblematic cases. Finally, we critically discuss the inherent shortcomings of the consultation approach as a model for indigenous participation in public decision-making and discuss the broader implications of our findings with regard to indigenous rights and natural resource governance.
Narrative Explanations: The Case for Causality
Authors: Gangl Georg
Published: September 2019

In this paper I argue that historiography employs causal narrative explanations just as other historical sciences such as evolutionary biology or paleontology do. There is a logic of explanation common to all these sciences that centers on causal explanation of unique and unrepeatable events. The explanandum of historiography can further be understood as mechanism in the sense developed by Stuart Glennan and others in recent years. However, causal explanation is not the only way historiography relates to the past. Arthur Danto has given us the theoretical tools to differentiate between causal narratives and conceptual colligations, with both playing a pivotal role in historiography even though Danto himself has not expressed that thought clearly.
A new species of Girdled Lizard (Squamata: Cordylidae) from the Serra da Neve Inselberg, Namibe Province, southwestern Angola
Authors: MARQUES MARIANA P. , CERÍACO LUIS M. P. , STANLEY EDWARD L. , BANDEIRA SUZANA A. , AGARWAL ISHAN , BAUER AARON M.
Published: September 2019

A new species of rupicolous girdled lizard is described from Serra da Neve Inselberg, Namibe Province, southwestern Angola. We sequenced two mitochondrial gene regions (16S and ND2) for the new species and compared these data with those previously published for other Cordylus species. The new species is genetically divergent from the closely related Cordylus machadoi and C. namakuiyus and morphologically distinguished by head scale arrangement, coloration, and osteological characters. Serra da Neve is the second highest peak in Angola and one of the most understudied areas of the country. The discovery of this new species highlights the importance of this inselberg for regional endemism and emphasizes the high conservation importance of the area.
A new species of Pimelodella Eigenmann & Eigenmann, 1888 (Siluriformes: Heptapteridae) from the Sierra Nevada de Santa Marta, Colombia
Authors: CONDE-SALDAÑA CRISTHIAN C. , ALBORNOZ-GARZÓN JUAN G. , GARCÍA-MELO JORGE E. , DERGAM JORGE A. , VILLA-NAVARRO FRANCISCO A.
Published: September 2019

A new species of Pimelodella is described from northern coastal drainages of the Sierra Nevada de Santa Marta (SNSM), Colombia. The new species is diagnosed from all trans-Andean congeners by the following unique combination of characters: head length 22.2–23.7% SL, bony interorbital width 17.6–21.6% HL, maxillary barbels length 53.0–68.3% SL, inner mental-barbels length 14.4–20.0% SL, body width 17.6–21.1% SL, dorsal-fin spine length 8.3–13.7% SL, dorsal-fin base 12.3–14.9% SL, pectoral-fin spine length 12.9-14.5% SL, pectoral-fin spine length without dentations on the distal posterior margin 21.6–29.8% in pectoral-fin spine length, maximum depth of dentations in posterior margin of pectoral-fin spine 1.40–1.68 times in the width of the spine at its base, adipose-fin base length 22.8–26.4% SL, caudal-peduncle depth 9.2–10.5% SL, 40 vertebrae, having a conspicuous paired dark brown stripe on the dorsal surface of body, extending from posterior margin of head to caudal-fin insertion and a wide dark brown midlateral stripe present. The isolated occurrence of this new taxon living in allopatry in coastal drainages of the SNSM could have interesting biogeographic implications for dispersal and vicariance processes of the ichthyofauna from northern South America.
Holomorphology of Kamimuria peppapiggia sp. n. (Plecoptera: Perlidae) from the foothills of Taihang Mountains, Henan Province of China
Authors: MO RAORAO , YAN YANHUA , WANG GUOQUAN , LI WEIHAI , MURÁNYI DÁVID
Published: September 2019

A new species of the species rich Asian perlid genus Kamimuria Klapálek, K. peppapiggia sp. n. from Henan Province of northwestern China, is described based on the male, female, larva, and egg. Relationship with congeners are discussed based on morphological characters. The new species is a possible remnant of the once diverse lowland aquatic fauna of the North China Plain.
Test of a Weather-Adaptive Dual-Resolution Hybrid Warn-on-Forecast Analysis and Forecast System for Several Severe Weather Events
Authors: Wang Yunheng , Gao Jidong , Skinner Patrick S. , Knopfmeier Kent , Jones Thomas , Creager Gerry , Heiselman Pamela L. , Wicker Louis J.
Published: September 2019

A real-time, weather adaptive, dual-resolution, hybrid Warn-on-Forecast (WoF) analysis and forecast system using the WRF-ARW forecast model has been developed and implemented. The system includes two components, an ensemble analysis and forecast component, and a deterministic hybrid three-dimensional ensemble–variational (3DEnVAR) analysis and forecast component. The goal of the system is to provide on-demand, ensemble-based, and physically consistent gridded analysis and forecast products to forecasters for making warning decisions. Both components, the WRF-DART system with 36 ensemble members and the hybrid 3DEnVAR system, assimilate radar data, satellite-retrieved cloud water path, and surface observations at 15-min intervals with dual-resolution capability. In the current hybrid configuration, one-way coupling of the two analysis systems is performed: ensemble covariances derived from the WRF-DART system are incorporated into the hybrid 3DEnVAR system with each data assimilation (DA) cycle. This study examines deterministic, 3-h forecasts launched from the hybrid 3DEnVAR analyses every 30 min for three severe weather events in 2017. The performance of the deterministic component is evaluated for four configurations: dual-resolution coupling, single-resolution coupling, forecasts initialized using a cloud analysis for reflectivity assimilation, and forecasts initialized from the WRF-DART ensemble mean. Quantitative and subjective evaluation of composite reflectivity and updraft helicity (UH) swath forecasts for the three events indicate that the dual-resolution strategy without the cloud analysis performs best among the four configurations and provides the most realistic prediction of reflectivity patterns and UH tracks.
Ensuring Success Among First-Generation, Low-Income, and Underserved Minority Students: Developing a Unified Community of Support
Authors: Holcombe Elizabeth , Kezar Adrianna
Published: September 2019

Recent research has demonstrated the value of comprehensive, integrated programs that combine and align several interventions to create a seamless learning environment for undergraduate students in STEM (science, technology, engineering, and mathematics). While there is emerging evidence of the value of these integrated programs for student success, there is little understanding of exactly how and why they are effective. This study of integrated programs at several California State University campuses indicates that successful integrated programs are effective because they create what we term a unified community of support for students, faculty, and staff. A unified community of support leverages structural changes to campus policies and practices to promote individual changes to faculty and staff knowledge, beliefs, actions, and relationships. This combination offers a unique and novel way of both organizing and conceptualizing student support within higher education, as most existing programs are based around either structural changes or individual support, rather than a mutually reinforcing combination of the two.
Telehealth coaching for rural-living young adult cancer survivors: A protocol
Authors: Price Jenson , Brunet Jennifer
Published: September 2019

Objective:

Young adult cancer survivors living in rural areas have reported barriers to participating in health behaviours due to their geographical location and the developmental milestones associated with their age. Existing health behaviour change interventions have generally been delivered face-to-face and have not been tailored to the preferences of young adults living in rural areas, thus not adequately addressing the needs of this population. To address these limitations, this trial aims to examine the feasibility and acceptability of a 12-week telehealth intervention drawing on self-determination theory to promote physical activity participation and fruit and vegetable consumption.

Design:

The intervention will be tested with young adults who are between the ages of 20 and 39 years, have completed primary treatment, live in an area with fewer than 35,000 inhabitants, are not currently meeting physical activity and fruit and vegetable consumption guidelines, have access to the Internet and audio-visual devices, are ambulatory and are able and willing to provide informed consent. The target sample size is 15.

Method:

Feasibility data will be collected by recording recommended outcomes throughout the trial. Additional feasibility data as well as acceptability data will be collected using an online questionnaire administered pre- and post-intervention and a semi-structured interview.

Results:

Results may inform the design and implementation of supportive care services for young adults, and potentially other adults living in rural areas who experience similar barriers to participating in health-promoting behaviours.

Conclusion:

This trial is one of the first to explore the feasibility and acceptability of a theory-based telehealth behaviour change intervention targeting young adult cancer survivors living in rural areas in order to mitigate the disease burden.
Who provides physical activity support in the workplace? Implications for peer led interventions
Authors: Edmunds Sarah , Sitch Matthew , Lowry Ruth
Published: September 2019

Objective:

Social support is one mechanism through which peer support physical activity (PA) interventions influence behaviour. The aim of this study was to explore the sources and characteristics of social support for PA among office-based work colleagues.

Design:

A sequential mixed-methods approach was used. First, social network analysis was utilised to map the sources of social support. Then interviews and focus groups were used to explore the characteristics of this support.

Setting:

One UK public sector employer in the south of England.

Method:

Using an online survey, 99 employees (40 men; Mage = 40 ± 12 years) reported their PA and named specific colleagues who provided four forms of social support for PA (emotional, informational, companionship, validation). Social network diagrams for each support network were visualised using UCINET and Netdraw. Individuals identified as most frequently providing support for PA participated in one-to-one interviews ( n = 6) to discuss their perspective on social support for PA in the workplace. Three focus groups explored the characteristics of social support for PA among employees identified within the networks as support seekers or disconnected. These qualitative data were analysed thematically.

Results:

Different patterns of relationships between employees were demonstrated for the four forms of support with informational support provided most frequently and validation least frequently. Qualitative data illustrate how each form of support was provided and received, as well as further perceived characteristics of social support.

Conclusion:

These findings could help inform the future selection and training of peer PA champions in workplace settings and more widely.
Studying Gaze Behavior to Compare Three Different Hazard Perception Tasks
Authors: Malone Sarah , Brünken Roland
Published: September 2019

Objective

The aim of the current study was to compare the traditional, verbal, and motoric tasks regarding their contributions to hazard perception measurement.

Background

Traditional hazard perception tasks require the participants to respond to filmed traffic conflicts in an imprecise way, such as by pressing a button. More sophisticated tasks include either verbal specification or motoric localization of the perceived hazards. The present study investigated the participants’ gaze behavior when they were provided with an identical set of traffic animations but were instructed to perform one of three types of hazard perception tasks.

Method

In an eye tracking study, 69 drivers were shown animated traffic scenarios and instructed to perform the traditional (press button), verbal, or speeded motoric localization hazard perception task. Eye tracking revealed whether and when the participant had fixated a certain hazard cue.

Results

The participants in the traditional task group were slower to fixate emerging hazards, but quicker to respond to them than the participants of the verbal and the motoric groups. As a specific benefit, the verbal task differentiated between different types of failures.

Conclusion

Additional verbal or speeded motoric localization tasks seem to have increased the participants’ alertness when watching the animations. The verbal task provides valuable additional information regarding the participants’ performance. To approximate real-life hazard perception ability, it is recommended that researchers and practitioners use a combination of different hazard perception tasks for assessment and training.
The Two-step Model of Clustered Democratization
Authors: Houle Christian , Kayser Mark A.
Published: September 2019

Does democratization diffuse? For over two decades, numerous studies have asserted that democratization diffuses across countries but recent research has challenged this claim. Most recently, work by Brancati and Lucardi has buttressed this null finding by demonstrating that an oft assumed mechanism for the diffusion of democratization—the diffusion of pro-democracy protests—lacks empirical support. We review this contribution in the context of recent research and pose the question: if democratization does not diffuse, then why does democratization cluster in time and space? The answer, we argue, is that democratization occurs in two steps. First, common shocks, economic or political, lead to regime collapse. Then, diffusion does emerge in a second step: new elites are more likely to install a democracy following a regime collapse if neighboring countries have recently democratized. We present evidence from democratic transitions in 125 autocracies between 1875 and 2014.