bluuebunny/crossref_metadata_2025 huggingface dataset:
S
-Nitrosoglutathione Reductase Is Essential for Protecting the Female Heart From Ischemia-Reperfusion Injury
Authors: Casin Kevin M. , Fallica Jonathan , Mackowski Nathan , Veenema Ryne J. , Chan Ashley , St. Paul Amanda , Zhu Guangshuo , Bedja Djahida , Biswal Shyam , Kohr Mark J.
Published: January 2019

Rationale:

Protein
S
-nitros(yl)ation (SNO) has been implicated as an essential mediator of nitric oxide-dependent cardioprotection. Compared with males, female hearts exhibit higher baseline levels of protein SNO and associated with this, reduced susceptibility to myocardial ischemia-reperfusion injury. Female hearts also exhibit enhanced
S
-nitrosoglutathione reductase (GSNO-R) activity, which would typically favor decreased SNO levels as GSNO-R mediates SNO catabolism.

Objective:

Because female hearts exhibit higher SNO levels, we hypothesized that GSNO-R is an essential component of sex-dependent cardioprotection in females.

Methods and Results:

Male and female wild-type mouse hearts were subjected to ex vivo ischemia-reperfusion injury with or without GSNO-R inhibition (N6022). Control female hearts exhibited enhanced functional recovery and decreased infarct size versus control males. Interestingly, GSNO-R inhibition reversed this sex disparity, significantly reducing injury in male hearts, and exacerbating injury in females. Similar results were obtained with male and female GSNO-R
−/−
hearts using ex vivo and in vivo models of ischemia-reperfusion injury. Assessment of SNO levels using SNO-resin assisted capture revealed an increase in total SNO levels with GSNO-R inhibition in males, whereas total SNO levels remained unchanged in females. However, we found that although GSNO-R inhibition significantly increased SNO at the cardioprotective Cys39 residue of nicotinamide adenine dinucleotide (NADH) dehydrogenase subunit 3 in males, SNO-NADH dehydrogenase subunit 3 levels were surprisingly reduced in N6022-treated female hearts. Because GSNO-R also acts as a formaldehyde dehydrogenase, we examined postischemic formaldehyde levels and found that they were nearly 2-fold higher in N6022-treated female hearts compared with nontreated hearts. Importantly, the mitochondrial aldehyde dehydrogenase 2 activator, Alda-1, rescued the phenotype in GSNO-R
−/−
female hearts, significantly reducing infarct size.

Conclusions:

These striking findings point to GSNO-R as a critical sex-dependent mediator of myocardial protein SNO and formaldehyde levels and further suggest that different therapeutic strategies may be required to combat ischemic heart disease in males and females.
Assessing the Causal Role of Body Mass Index on Cardiovascular Health in Young Adults
Authors: Wade Kaitlin H. , Chiesa Scott T. , Hughes Alun D. , Chaturvedi Nish , Charakida Marietta , Rapala Alicja , Muthurangu Vivek , Khan Tauseef , Finer Nicholas , Sattar Naveed , Howe Laura D. , Fraser Abigail , Lawlor Debbie A. , Davey Smith George , Deanfield John E. , Timpson Nicholas J.
Published: January 2019

Background:

Body mass index (BMI) has been suggested to be causally related to cardiovascular health in mid-to-late life, but this has not been explored systematically at younger ages—nor with detailed cardiovascular phenotyping. Recall-by-Genotype (RbG) is an approach that enables the collection of precise phenotypic measures in smaller studies, while maintaining statistical power and ability for causal inference.

Methods:

In this study, we used a combination of conventional multivariable regression analysis, Mendelian randomization (MR), and subsample RbG methodologies to estimate the causal effect of BMI on gross-level and detailed cardiovascular health in healthy participants from the Avon Longitudinal Study of Parents and Children at age 17 years (N=1420–3108 for different outcomes) and an independent sample from the same cohort (for RbG) study at age 21 years (N=386–418).

Results:

In both MR and RbG analyses, results suggested that higher BMI causes higher blood pressure and left ventricular mass index in young adults (eg, difference in left ventricular mass index per 1 kg/m
2
using MR: 1.07 g/m
2.7
; 95% CI, 0.62–1.52;
P
=3.87×10
-06
and per 3.58 kg/m
2
using RbG: 1.65 g/m
2.7
; 95% CI, 0.83–2.47;
P
=0.0001). Additionally, RbG results suggested a causal role of higher BMI on higher stroke volume (difference per 3.58 kg/m
2
: 1.49 mL/m
2.04
; 95% CI, 0.62–2.35;
P
=0.001) and cardiac output (difference per 3.58 kg/m
2
: 0.11 L·min
-1
·m
-1.83
; 95% CI, 0.03–0.19;
P
=0.01) but no strong evidence for a causal role on systemic vascular resistance or total arterial compliance. Neither analysis supported a causal role of higher BMI on heart rate.

Conclusions:

Complementary MR and RbG causal methodologies, together with a range of sensitivity analyses, suggest that higher BMI is likely to cause worse cardiovascular health, specifically higher blood pressure and left ventricular mass index, even in youth. Higher BMI also resulted in increased cardiac output in the RbG study, which appeared to be solely driven by stroke volume, as neither MR nor RbG analyses suggested a causal effect of BMI on heart rate. These consistent results support efforts to reduce BMI from a young age to prevent later adverse cardiovascular health and illustrate the potential for phenotypic resolution with maintained analytic power using RbG.
Determination and Interpretation of the QT Interval
Authors: Vink Arja Suzanne , Neumann Benjamin , Lieve Krystien V.V. , Sinner Moritz F. , Hofman Nynke , el Kadi Soufiane , Schoenmaker Melissa H.A. , Slaghekke Hanneke M.J. , de Jong Jonas S.S.G. , Clur Sally-Ann B. , Blom Nico A. , Kääb Stefan , Wilde Arthur A.M. , Postema Pieter G.
Published: January 2019

Background:

Long QT syndrome (LQTS) is associated with potentially fatal arrhythmias. Treatment is very effective, but its diagnosis may be challenging. Importantly, different methods are used to assess the QT interval, which makes its recognition difficult. QT experts advocate manual measurements with the tangent or threshold method. However, differences between these methods and their performance in LQTS diagnosis have not been established. We aimed to assess similarities and differences between these 2 methods for QT interval analysis to aid in accurate QT assessment for LQTS.

Methods:

Patients with a confirmed pathogenic variant in
KCNQ1
(LQT1),
KCNH2
(LQT2), or
SCN5A
(LQT3) genes and their family members were included. Genotype-positive patients were identified as LQTS cases and genotype-negative family members as controls. ECGs were analyzed with both methods, providing inter- and intrareader validity and diagnostic accuracy. Cutoff values based on control population’s 95th and 99th percentiles, and LQTS-patients’ 1st and 5th percentiles were established based on the method to correct for heart rate, age, and sex.

Results:

We included 1484 individuals from 265 families, aged 33±21 years and 55% females. In the total cohort, QT
Tangent
was 10.4 ms shorter compared with QT
Threshold
(95% limits of agreement±20.5 ms,
P
<0.0001). For all genotypes, QT
Tangent
was shorter than QT
Threshold
(
P
<0.0001), but this was less pronounced in LQT2. Both methods yielded a high inter- and intrareader validity (intraclass correlation coefficient >0.96), and a high diagnostic accuracy (area under the curve >0.84). Using the current guideline cutoff (QTc interval 480 ms), both methods had similar specificity but yielded a different sensitivity. QTc interval cutoff values of QT
Tangent
were lower compared with QT
Threshold
and different depending on the correction for heart rate, age, and sex.

Conclusion:

The QT interval varies depending on the method used for its assessment, yet both methods have a high validity and can both be used in diagnosing LQTS. However, for diagnostic purposes current guideline cutoff values yield different results for these 2 methods and could result in inappropriate reassurance or treatment. Adjusted cutoff values are therefore specified for method, correction formula, age, and sex. In addition, a freely accessible online probability calculator for LQTS (
www.QTcalculator.org
) has been made available as an aid in the interpretation of the QT interval.
Right Ventricular Fibrosis
Authors: Andersen Stine , Nielsen-Kudsk Jens Erik , Vonk Noordegraaf Anton , de Man Frances S.
Published: January 2019

The role of right ventricular (RV) fibrosis in pulmonary hypertension (PH) remains a subject of ongoing discussion. Alterations of the collagen network of the extracellular matrix may help prevent ventricular dilatation in the pressure-overloaded RV. At the same time, fibrosis impairs cardiac function, and a growing body of experimental data suggests that fibrosis plays a crucial role in the development of RV failure. In idiopathic pulmonary arterial hypertension and chronic thromboembolic PH, the RV is exposed to a ≈5 times increased afterload, which makes these conditions excellent models for studying the impact of pressure overload on RV structure. With this review, we present clinical evidence of RV fibrosis in idiopathic pulmonary arterial hypertension and chronic thromboembolic PH, explore the correlation between fibrosis and RV function, and discuss the clinical relevance of RV fibrosis in patients with PH. We postulate that RV fibrosis has a dual role in patients with pressure-overloaded RVs of idiopathic pulmonary arterial hypertension and chronic thromboembolic PH: as part of an adaptive response to prevent cardiomyocyte overstretch and to maintain RV shape for optimal function, and as part of a maladaptive response that increases diastolic stiffness, perturbs cardiomyocyte excitation-contraction coupling, and disrupts the coordination of myocardial contraction. Finally, we discuss potential novel therapeutic strategies and describe more sensitive techniques to quantify RV fibrosis, which may be used to clarify the causal relation between RV fibrosis and RV function in future research.
New Strategies for Surgical Myocardial Revascularization
Authors: Gaudino Mario , Bakaeen Faisal , Davierwala Piroze , Di Franco Antonino , Fremes Stephen E. , Patel Nirav , Puskas John D. , Ruel Marc , Torregrossa Gianluca , Vallely Michael , Taggart David P. ,   the ATLANTIC (Arterial Grafting International Consortium) Alliance
Published: January 2019

We summarize the evidence on the new strategies for coronary artery bypass grafting (CABG). Hybrid CABG implies surgical grafting of the left anterior descending artery and percutaneous treatment of the other target vessels, with the promise of combining the durable benefits of surgery with the less invasive approach of percutaneous coronary interventions. Robotic CABG and minimally invasive CABG are performed through minimal incision or port access with dedicated equipment and instruments. Anaortic coronary artery bypass refers to off-pump CABG using only in-situ grafts. The use of multiple arterial grafts has been shown to improve patency and is potentially associated with better clinical outcomes. All these techniques require dedicated training and are more complex than conventional CABG but can significantly improve the results of surgery. Validation of the results of these new approaches in large randomized trials is a priority for the surgical community.
Probing the Virtual Proteome to Identify Novel Disease Biomarkers
Authors: Mosley Jonathan D. , Benson Mark D. , Smith J. Gustav , Melander Olle , Ngo Debby , Shaffer Christian M. , Ferguson Jane F. , Herzig Matthew S. , McCarty Catherine A. , Chute Christopher G. , Jarvik Gail P. , Gordon Adam S. , Palmer Melody R. , Crosslin David R. , Larson Eric B. , Carrell David S. , Kullo Iftikhar J. , Pacheco Jennifer A. , Peissig Peggy L. , Brilliant Murray H. , Kitchner Terrie E. , Linneman James G. , Namjou Bahram , Williams Marc S. , Ritchie Marylyn D. , Borthwick Kenneth M. , Kiryluk Krzysztof , Mentch Frank D. , Sleiman Patrick M. , Karlson Elizabeth W. , Verma Shefali S. , Zhu Yineng , Vasan Ramachandran S. , Yang Qiong , Denny Josh C. , Roden Dan M. , Gerszten Robert E. , Wang Thomas J.
Published: January 2019

Background:

Proteomic approaches allow measurement of thousands of proteins in a single specimen, which can accelerate biomarker discovery. However, applying these technologies to massive biobanks is not currently feasible because of the practical barriers and costs of implementing such assays at scale. To overcome these challenges, we used a “virtual proteomic” approach, linking genetically predicted protein levels to clinical diagnoses in >40 000 individuals.

Methods:

We used genome-wide association data from the Framingham Heart Study (n=759) to construct genetic predictors for 1129 plasma protein levels. We validated the genetic predictors for 268 proteins and used them to compute predicted protein levels in 41 288 genotyped individuals in the Electronic Medical Records and Genomics (eMERGE) cohort. We tested associations for each predicted protein with 1128 clinical phenotypes. Lead associations were validated with directly measured protein levels and either low-density lipoprotein cholesterol or subclinical atherosclerosis in the MDCS (Malmö Diet and Cancer Study; n=651).

Results:

In the virtual proteomic analysis in eMERGE, 55 proteins were associated with 89 distinct diagnoses at a false discovery rate q<0.1. Among these, 13 associations involved lipid (n=7) or atherosclerosis (n=6) phenotypes. We tested each association for validation in MDCS using directly measured protein levels. At Bonferroni-adjusted significance thresholds, levels of apolipoprotein E isoforms were associated with hyperlipidemia, and circulating C-type lectin domain family 1 member B and platelet-derived growth factor receptor-β predicted subclinical atherosclerosis. Odds ratios for carotid atherosclerosis were 1.31 (95% CI, 1.08–1.58;
P
=0.006) per 1-SD increment in C-type lectin domain family 1 member B and 0.79 (0.66–0.94;
P
=0.008) per 1-SD increment in platelet-derived growth factor receptor-β.

Conclusions:

We demonstrate a biomarker discovery paradigm to identify candidate biomarkers of cardiovascular and other diseases.
Safely Identifying Emergency Department Patients With Acute Chest Pain for Early Discharge
Authors: Mahler Simon A. , Lenoir Kristin M. , Wells Brian J. , Burke Gregory L. , Duncan Pamela W. , Case L. Douglas , Herrington David M. , Diaz-Garelli Jose-Franck , Futrell Wendell M. , Hiestand Brian C. , Miller Chadwick D.
Published: January 2019

Background:

The HEART Pathway (history, ECG, age, risk factors, and initial troponin) is an accelerated diagnostic protocol designed to identify low-risk emergency department patients with chest pain for early discharge without stress testing or angiography. The objective of this study was to determine whether implementation of the HEART Pathway is safe (30-day death and myocardial infarction rate <1% in low-risk patients) and effective (reduces 30-day hospitalizations) in emergency department patients with possible acute coronary syndrome.

Methods:

A prospective pre-post study was conducted at 3 US sites among 8474 adult emergency department patients with possible acute coronary syndrome. Patients included were ≥21 years old, investigated for possible acute coronary syndrome, and had no evidence of ST-segment–elevation myocardial infarction on ECG. Accrual occurred for 12 months before and after HEART Pathway implementation from November 2013 to January 2016. The HEART Pathway accelerated diagnostic protocol was integrated into the electronic health record at each site as an interactive clinical decision support tool. After accelerated diagnostic protocol integration, ED providers prospectively used the HEART Pathway to identify patients with possible acute coronary syndrome as low risk (appropriate for early discharge without stress testing or angiography) or non-low risk (appropriate for further in-hospital evaluation). The primary safety and effectiveness outcomes, death, and myocardial infarction (MI) and hospitalization rates at 30 days were determined from health records, insurance claims, and death index data.

Results:

Preimplementation and postimplementation cohorts included 3713 and 4761 patients, respectively. The HEART Pathway identified 30.7% as low risk; 0.4% of these patients experienced death or MI within 30 days. Hospitalization at 30 days was reduced by 6% in the postimplementation versus preimplementation cohort (55.6% versus 61.6%; adjusted odds ratio, 0.79; 95% CI, 0.71–0.87). During the index visit, more MIs were detected in the postimplementation cohort (6.6% versus 5.7%; adjusted odds ratio, 1.36; 95% CI, 1.12–1.65). Rates of death or MI during follow-up were similar (1.1% versus 1.3%; adjusted odds ratio, 0.88; 95% CI, 0.58–1.33).

Conclusions:

HEART Pathway implementation was associated with decreased hospitalizations, increased identification of index visit MIs, and a very low death and MI rate among low-risk patients. These findings support use of the HEART Pathway to identify low-risk patients who can be safely discharged without stress testing or angiography.

Clinical Trial Registration:

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT02056964.
Aldosterone and 18-Oxocortisol Coaccumulation in Aldosterone-Producing Lesions
Authors: Sugiura Yuki , Takeo Emi , Shimma Shuichi , Yokota Mai , Higashi Tatsuya , Seki Tsugio , Mizuno Yosuke , Oya Mototsugu , Kosaka Takeo , Omura Masao , Nishikawa Tetsuo , Suematsu Makoto , Nishimoto Koshiro
Published: January 2019

Primary aldosteronism is a secondary hypertensive disease caused by autonomous aldosterone production that often caused by an aldosterone-producing adenoma (APA). Immunohistochemistry of aldosterone synthase (CYP11B2) shows the presence of aldosterone-producing cell clusters (APCCs) even in non-primary aldosteronism adult adrenal cortex. An APCC-like structure also exists as possible APCC-to-APA transitional lesions (a speculative designation) in primary aldosteronism adrenals. However, whether APCCs produce aldosterone or 18-oxocortisol, a potential serum marker of APA, remains unknown because of lack of technology to visualize adrenocorticosteroids on tissue sections. To address this obstacle, in this study, we used highly sensitive Fourier transform ion cyclotron resonance mass spectrometry to image various adrenocorticosteroids, including 18-oxocortisol, in adrenal tissue sections from 8 primary aldosteronism patients with APCC (cases 1–4), possible APCC-to-APA transitional lesions (case 5), and APA (cases 6–8). Further analyses by tandem mass spectrometry imaging allowed us to differentially visualize aldosterone from cortisone, which share identical mass-to-charge ratio value (
m/z
). In conclusion, these advanced imaging techniques revealed that aldosterone and 18-oxocortisol coaccumulated within CYP11B2-expressing lesions. These imaging outcomes along with a growing body of aldosterone research led us to build a progressive development hypothesis of an aldosterone-producing pathology in the adrenal glands.
Therapeutic Vaccine Against S100A9 (S100 Calcium-Binding Protein A9) Inhibits Thrombosis Without Increasing the Risk of Bleeding in Ischemic Stroke in Mice
Authors: Kawano Tomohiro , Shimamura Munehisa , Nakagami Hironori , Iso Tatsuya , Koriyama Hiroshi , Takeda Shuko , Baba Kosuke , Sasaki Tsutomu , Sakaguchi Manabu , Morishita Ryuichi , Mochizuki Hideki
Published: January 2019

Decreased adherence to daily ingestion of antiplatelet drugs is a critical issue, increasing mortality and morbidity in poststroke patients. As vaccination could be a promising approach to solving this, we designed an antiplatelet vaccine that inhibited S100A9 (S100 calcium-binding protein A9)/CD36 (cluster of differentiation 36) signaling in platelets, which was reported to be a key signal in arterial thrombosis, but not hemostasis. Immunization with this vaccine induced a sustainable increase in the anti-S100A9 antibody titer for >2 months and an additional booster immunization enhanced the antibody production further. The middle cerebral artery occlusion time was successfully prolonged in the vaccinated mice, which was comparable to that in mice treated with clopidogrel. The antithrombotic effect lasted for 84 days after the last vaccination, as well as after the booster immunization. Importantly, the bleeding time was not affected in the immunized mice. The antithrombotic effect was also observed in the common carotid artery, which was similar to that found in CD36
−/−
mice. Vascular injury increased the expression of S100A9 in the serum and phosphorylation of JNK (c-Jun N-terminal kinase) and VAV1 in the platelets, but these increases were inhibited in the immunized mice. Moreover, the S100A9 vaccine did not induce cell-mediated autoimmunity, as demonstrated by the enzyme-linked immunosorbent spot assay. Thus, immunization with the S100A9 vaccine resulted in long-term inhibition of thrombus formation through inhibition of increased S100A9/CD36 signaling without risk of bleeding or adverse autoimmune responses. Vaccination against S100A9 might be a novel therapy to prevent recurrent ischemic stroke.
Improving Hypertension Control in Primary Care With the Measure Accurately, Act Rapidly, and Partner With Patients Protocol
Authors: Egan Brent M. , Sutherland Susan E. , Rakotz Michael , Yang Jianing , Hanlin R. Bruce , Davis Robert A. , Wozniak Gregory
Published: January 2019

Better blood pressure (BP; mm Hg) control is a pivotal national strategy for preventing cardiovascular events. Measure accurately, Act rapidly, and Partner with patients (MAP) with practice facilitation improved BP control (<140/<90 mm Hg) from 61.2% to 89.8% during a 6-month pilot study in one primary care clinic. Current study objectives included evaluating the 6-month MAP framework in 16 Family Medicine Clinics and then withdrawing practice facilitation and determining whether better hypertension control persisted at 12 months since short-term improvements often decline by 1 year. Measure accurately included staff training in attended (intake) BP measurement and unattended automated office BP when intake BP was ≥140/≥90 mm Hg. Act rapidly (therapeutic inertia) included protocol-guided escalation of antihypertensive medications when office BP was ≥140/≥90 mm Hg. Partner with patients (systolic BP decline/therapeutic intensification) included shared decision making, BP self-monitoring, and affordable medications. Study data were obtained from electronic records. In 16 787 hypertensive adults (mean, 61.2 years; 54.1% women; 46.0% Medicare) with visits at baseline and first 6 months, BP control improved from 64.4% at baseline to 74.3% (
P
<0.001) at 6 and 73.6% (
P
<0.001) at 12 months. At the first MAP visit, among adults with uncontrolled baseline BP and no medication changes (n=3654), measure accurately resulted in 11.1/5.1 mm Hg lower BP. During the first 6 months of MAP, therapeutic inertia fell (52.0% versus 49.5%;
P
=0.01), and systolic BP decreased more per therapeutic intensification (−5.4 to −12.7;
P
<0.001). MAP supports a key national strategy for cardiovascular disease prevention through rapid and sustained improvement in hypertension control, largely reflecting measuring accurately and partnering with patients.
Hypertension Treatment Rates and Health Care Worker Density
Authors: Vedanthan Rajesh , Ray Mondira , Fuster Valentin , Magenheim Ellen
Published: January 2019

Elevated blood pressure is the leading cause of death worldwide; however, treatment and control rates for hypertension are low. Here, we analyze the relationship between physician and nurse density and hypertension treatment rates worldwide. Data on hypertension treatment rates were collected from the STEPwise approach to Surveillance country reports, individual studies resulting from a PubMed search for articles published between 1990 and 2010, and manual search of the reference lists of extracted studies. Data on health care worker density were obtained from the Global Atlas of the Health Workforce. We controlled for a variety of variables related to population characteristics and access to health care, data obtained from the World Bank, World Development Indicators, United Nations, and World Health Organization. We used clustering of SEs at the country level. Full data were available for 154 hypertension treatment rate values representing 68 countries between 1990 and 2010. Hypertension treatment rate ranged from 3.4% to 82.5%, with higher treatment rates associated with higher income classification. Physician and nurse/midwife generally increased with income classification. Total healthcare worker density was significantly associated with hypertension treatment rate in the unadjusted model (
P
<0.001); however, only nurse density remained significant in the fully adjusted model (
P
=0.050). These analyses suggest that nurse density, not physician density, explains most of the relationship with hypertension treatment rate and remains significant even after adjusting for other independent variables. These results have important implications for health policy, health system design, and program implementation.
Trust in Community-Engaged Research Partnerships: A Methodological Overview of Designing a Multisite Clinical and Translational Science Awards (CTSA) Initiative
Authors: Kim Mimi M. , Cheney Ann , Black Anita , Thorpe Roland J. , Cene Crystal Wiley , Dave Guarav J. , Schaal Jennifer , Vassar Stefanie , Ruktanonchai Corrine , Frerichs Leah , Young Tiffany , Jones Jennifer , Burke Jessica , Varma Deepthi , Striley Catherine , Cottler Linda , Brown Arleen , Sullivan Greer , Corbie-Smith Giselle
Published: January 2019

Community-engaged research (CEnR) builds on the strengths of the Clinical and Translational Science Awards (CTSA) framework to address health in underserved and minority communities. There is a paucity of studies that identify the process from which trust develops in CEnR partnerships. This study responds to the need for empirical investigation of building and maintaining trust from a multistakeholder perspective. We conducted a multi-institutional pilot study using concept mapping with to better understand how trust, a critical outcome of CEnR partnerships, can act as “social capital.” Concept mapping was used to collect data from the three stakeholder groups: community, health-care, and academic research partners across three CTSAs. Concept mapping is a mixed-methods approach that allows participants to brainstorm and identify factors that contribute to a concept and describe ways in which those factors relate to each other. This study offers important insights on developing an initial set of trust measures that can be used across CTSAs to understand differences and similarities in conceptualization of trust among key stakeholder groups, track changes in public trust in research, identify both positive and negative aspects of trust, identify characteristics that maintain trust, and inform the direction for future research.
Transforming Rehabilitation: The impact of austerity and privatisation on day-to-day cultures and working practices in ‘probation’
Authors: Walker Samantha , Annison Jill , Beckett Sharon
Published: January 2019

Viewed as a culmination of broader neoliberal governance within the UK, this paper examines the impact of the government’s Transforming Rehabilitation (TR) agenda on day-to-day working cultures at the frontline of probation work. TR has brought with it extensive structural and cultural changes to probation work in England and Wales. Once a single public-sector service with a social welfare ethos of ‘advise, assist and befriend’, probation has been dismantled, partially privatised and culturally transformed into a collection of fragmented, target-driven organisations, divided according to risk and with an official rhetoric emphasising public protection. The implications of TR are now starting to surface. While much of this attention has focused on the impact of TR on both the supervision of offenders and in terms of public protection, less research has been conducted on how these organisational changes have impacted upon staff. Drawing upon findings from qualitative research, this article suggests that deepening cuts, precarious working environments, and increasingly unmanageable caseloads inflict upon staff what we consider to be a pervasive form of systemic workplace harm, resulting in mental health issues, stress, and professional dissatisfaction.
The Effect of Reminiscence Therapy With Internet-Based Videos on Cognitive Status and Apathy of Older People With Mild Dementia
Authors: İnel Manav Ayşe , Simsek Nuray
Published: January 2019

This study was carried out to assess the effects of reminiscence therapy that was supported with internet-based videos on the cognitive condition and apathy levels of older people with mild dementia living in nursing homes. This randomized controlled experimental study was conducted between May 15, 2016, and August 25, 2016, in two nursing homes in Adana, Turkey. A total of 32 people participated in this study, 16 individuals were in the intervention group and 16 individuals were in the control group. The data were collected using a Personal Information Form, the Standardized Mini-Mental State Examination (SMMSE) test, and the Apathy Rating Scale (ARS) Self-assessment Form. The individuals in the intervention group received group reminiscence therapy involving internet-based videos for 60 minutes once a week for 3 months. During this period, 25 to 30 minutes of unstructured interviews were carried out with individuals in the control group. The data were analyzed using descriptive statistics, Student t test, the Mann-Whitney U test, and Wilcoxon signed rank test. In this study, a significant difference was found between experimental and control groups’ posttest mean scores on the SMMSE test and ARS ( P < .01). The experimental group’s SMMSE test and ARS posttest mean scores were higher than those of the control group ( P < .01). This study found that group reminiscence therapy using internet-based videos improved the cognitive functions and apathy levels of older people with mild dementia of the Alzheimer type. It is recommended that group reminiscence therapy studies with Internet-based videos be conducted in care institutions that are responsible for managing older people with mild dementia of the Alzheimer type.
My trip in my words: Subjectivities, time(s) and mobilities in slow travel blogs
Authors: Sales Oliveira Catarina
Published: January 2019

With roots in the slow movement, slow travel is an emerging trend. In slow travel, the use of clean transportation is identified by some authors as a distinguishing characteristic of the concept; however, diversity of choices and profiles seems to contradict this assessment. To date, typologies of slow travellers are still scarce and any connections with mobility and time remain to be investigated, particularly concerning slow travel literature. In this article, using a qualitative approach, we analysed the discourse of a set of slow travellers who author a travel blog to understand their experiences, the interconnection between (slow) travel and blogging and how they represent time and mobility. The results indicate that slow travel blogs are not only a robust source of information concerning the emergence of this travel mode but also a product and producer of it, in a dialectic process. The subjective perceptions and representations of slowness are a central element of the discourse framing the travel experience. Contradictions between the slowness of the travel mode and the instantaneity of the blog emerged, and an interpretation is proposed, based on the voices of the travellers/bloggers.
“A group that’s just women for women”: Feminist affordances of private Facebook groups for professionals
Authors: Pruchniewska Urszula
Published: January 2019

Women across a range of industries are creating women-only private Facebook groups for professional support, networking opportunities, and career development. Through interviews with 26 women, this research shows how private Facebook groups provide affordances for creating spaces reminiscent of second-wave consciousness-raising groups. Within these groups, separate from cisgender men, women discuss their work experiences and share advice, leading to changes for women beyond the groups’ borders. Thus, private Facebook groups for professional women support feminist practices despite not being labeled as explicitly feminist. However, these activities are limited in their usefulness for the wider feminist project by the exclusion of some women across lines of difference such as race, class, and age. This study illustrates empirically how social media is used for everyday politics, contributing to understandings of the digital fourth wave of the women’s movement.
Genetic determinants of blood pressure traits are associated with carotid arterial thickening and plaque formation in patients with type 2 diabetes
Authors: Engelbrechtsen Line , Appel Vincent E , Schnurr Theresia M , Lundby-Christensen Louise , Skaaby Thea , Linneberg Allan , Drivsholm Thomas , Witte Daniel R , Jorgensen Marit E , Grarup Niels , Pedersen Oluf , Hansen Torben , Vestergaard Henrik ,   The CIMT Trial Group10
Published: January 2019

Objectives:

The aim of this study is to explore the contribution of genetically driven cardiometabolic risk factors for development of carotid arterial thickening in patients with type 2 diabetes.

Methods:

In total, 12 genetic risk scores for blood pressure, blood lipids and glycaemic traits were constructed. The genetic risk scores were tested for association with carotid intima-media thickness and plaques in patients with type 2 diabetes ( n = 401) and in non-diabetic individuals ( n = 648) and for association with glucose levels in two population-based cohorts ( n = 1328 and n = 6161).

Results:

In patients with type 2 diabetes, the genetic risk scores for pulse pressure were positively associated with plaque formation ( β = 0.036 ± 0.01 standard deviation/allele, p = 0.003). The genetic risk score for diastolic blood pressure was negatively associated with carotid intima-media thickness ( β = –0.037 ± 0.01 standard deviation/allele, p = 0.005), although not significant after correction for multiple testing ( p < 0.0042). In a meta-analysis of individuals with and without type 2 diabetes, the high-density lipoprotein genetic risk scores showed a trend towards an inverse association with carotid intima-media thickness and plaques, while the low-density lipoprotein genetic risk scores showed a trend towards a positive association with plaque formation but did reach the statistical threshold.

Conclusion:

Genetic loci for pulse pressure are associated with plaque formation among patients with type 2 diabetes, suggesting an underlying genetic contribution to arterial stiffening and atherosclerosis.
The involvement of mitochondrial fission in maintenance of the stemness of bone marrow mesenchymal stem cells
Authors: Feng Xiaorong , Zhang Wenjing , Yin Wen , Kang Y James
Published: January 2019

Mitochondrial dynamics, a complicated cellular process consisting of mitochondrial fusion and fission, has been suggested to be involved in regulating the stemness of bone marrow mesenchymal stem cells (BMSCs). This study was undertaken to explore the relationship between mitochondrial dynamics and the maintenance of BMSCs’ stemness. Rat BMSCs were treated with fibroblast growth factor 2 (FGF2) and epithelial growth factor (EGF) to induce differentiation. Mitochondrial dynamics was determined by mitochondrial length observed by confocal microscope and DLP1 (a protein promoting mitochondrial fission), OPA1 (a protein promoting mitochondrial fusion) expression revealed by Western blotting analysis. BMSCs’ stemness was determined by flow cytometry and osteogenic/adipogenic differentiation ability. We found that in the process of BMSCs differentiation, mitochondrial length was increased, along with a decreased protein level of DLP1 and an increased protein level of OPA1 in the mitochondria, indicating a shift toward mitochondrial fusion in BMSCs during differentiation. Notably, when the mitochondrial fission was inhibited by Mdivi-1, the stemness marker, CD90, was deceased along with the reduction of DLP1 expression. Under the same condition, the potential of BMSCs to be induced into adipocytes or osteocytes was decreased. Correspondingly, when BMSCs were treated with tyrphostin A9, a reagent promoting mitochondrial fission by increasing DLP1, the stemness marker, CD54, was increased with an increased potential of BMSCs to be induced into adipocytes or osteocytes. Hence, our results demonstrated that mitochondrial fission contributed to the maintenance of BMSCs’ stemness.

Impact statement

How to maintain the stemness of bone marrow mesenchymal stem cells (BMSCs) in cultures is a long-standing question. The present study found that mitochondrial dynamics affects the stemness of BMSCs in cultures and the retaining of mitochondrial fission enhances the stemness of BMSCs. This work thus provides a novel insight into strategic approaches to maintain the stemness of BMSCs in cultures in relation to the clinical application of bone-marrow stem cells.
Lower Body Acceleration and Muscular Responses to Rotational and Vertical Whole-Body Vibration at Different Frequencies and Amplitudes
Authors: Zaidell Lisa N. , Pollock Ross D. , James Darren C. , Bowtell Joanna L. , Newham Di J. , Sumners David P. , Mileva Katya N.
Published: January 2019

Aim:

The aim of this study was to characterize acceleration transmission and neuromuscular responses to rotational vibration (RV) and vertical vibration (VV) at different frequencies and amplitudes.

Methods:

Twelve healthy males completed 2 experimental trials (RV vs VV) during which vibration was delivered during either squatting (30°; RV vs VV) or standing (RV only) with 20, 25, and 30 Hz, at 1.5 and 3.0 mm peak-to-peak amplitude. Vibration-induced accelerations were assessed with triaxial accelerometers mounted on the platform and bony landmarks at ankle, knee, and lumbar spine.

Results:

At all frequency/amplitude combinations, accelerations at the ankle were greater during RV (all P < .03) with the greatest difference observed at 30 Hz, 1.5 mm. Transmission of RV was also influenced by body posture (standing vs squatting, P < .03). Irrespective of vibration type, vibration transmission to all skeletal sites was generally greater at higher amplitudes but not at higher frequencies, especially above the ankle joint. Acceleration at the lumbar spine increased with greater vibration amplitude but not frequency and was highest with RV during standing.

Conclusions/Implications:

The transmission of vibration during whole-body vibration (WBV) is dependent on intensity and direction of vibration as well as body posture. For targeted mechanical loading at the lumbar spine, RV of higher amplitude and lower frequency vibration while standing is recommended. These results will assist with the prescription of WBV to achieve desired levels of mechanical loading at specific sites in the human body.
Academic oncology clinicians’ understanding of biosimilars and information needed before prescribing
Authors: Cook John W. , McGrath Megan K. , Dixon Margie D. , Switchenko Jeffrey M. , Harvey R. Donald , Pentz Rebecca D.
Published: January 2019

Background:

With increasing numbers of oncology biosimilars in the approval pipeline, it is important to investigate oncology clinicians’ understanding of biosimilars and what information they need prior to adoption.

Methods:

Between January and May 2018, 77 oncology clinicians (52 physicians, 16 pharmacists, and 9 advanced practice providers) completed a survey covering three domains: clinician understanding, prescription preferences, and patient involvement. An in-depth interview was designed based on themes identified in the first 50 surveys: cost, safety and efficacy, patient preference, and disease stage. Participants were chosen to participate in the interview based on outlying responses to survey questions.

Results:

When asked to define a biosimilar, 74% (57/77) of respondents could not give a satisfactory definition, and 40.3% (31/77) considered a biosimilar the same as a generic drug. The most important factor in biosimilar prescription was safety and efficacy (4.51 out of 5) followed closely by cost differences (4.34 out of 5). A 40% increase (53.2–94.8%) in clinicians’ prescribing likelihood was seen after a biosimilar is designated as interchangeable. Participants in this study were split regarding the importance of shared decision-making with patients [50.7% (39/77) important or extremely important, 39.0% (30/77) somewhat or not at all important]. Clinicians were also split concerning the role that pharmacists should play in the decision to prescribe or substitute biosimilars.

Conclusion:

Understanding of biosimilars is low, and educational needs are high. The information that clinicians deem important to assess, such as safety, efficacy and cost, will need to be provided before they are comfortable prescribing biosimilars.
The African Prospective study on the Early Detection and Identification of Cardiovascular disease and Hypertension (African-PREDICT): Design, recruitment and initial examination
Authors: Schutte Aletta E , Gona Philimon N , Delles Christian , Uys Aletta S , Burger Adele , Mels Catharina MC , Kruger Ruan , Smith Wayne , Fourie Carla MT , Botha Shani , Lammertyn Leandi , van Rooyen Johannes M , Gafane-Matemane Lebo F , Mokwatsi Gontse G , Breet Yolandi , Kruger H Salome , Zyl Tertia van , Pieters Marlien , Zandberg Lizelle , Louw Roan , Moss Sarah J , Khumalo Itumeleng P , Huisman Hugo W
Published: January 2019

Background

Globally hypertension is stabilising, but in sub-Saharan Africa the incidence of hypertension remains on an increase. Although this might be attributed to poor healthcare and ineffective antihypertensive treatment, there is a limited understanding of population and individual-specific cardiovascular pathophysiology – necessary for effective prevention and treatment strategies in Africa. As there is a lack of longitudinal studies tracking the early pathophysiological development of hypertension in black populations, the African-PREDICT study was initiated. The purpose of this paper is to describe the detailed methodology and baseline cohort profile of the study.

Methods and results

From 2013 to 2017, the study included 1202 black ( N = 606) and white ( N = 596) men and women (aged 20–30 years) from South Africa – screened to be healthy and clinic normotensive. At baseline, and each 5-year follow-up examination, detailed measures of health behaviours, cardiovascular profile and organ damage are taken. Also, comprehensive biological sampling for the ‘omics’ and biomarkers is performed. Overall, the baseline black and white cohort presented with similar ages, clinic and 24-hour blood pressures, but black adults had lower socioeconomic status and higher central systolic blood pressure than white individuals.

Conclusions

The prospective African-PREDICT study in young black and white adults will contribute to a clear understanding of early cardiovascular disease development.
Treatment of refractory hemophagocytic lymphohistiocytosis with emapalumab despite severe concurrent infections
Authors: Lounder Dana T. , Bin Qiong , de Min Cristina , Jordan Michael B.
Published: January 2019

Key Points

Neutralization of IFN-γ with emapalumab can reverse severe, refractory hemophagocytic lymphohistiocytosis. Neutralizing IFN-γ did not impair control of multiple viral and other infections in a severely ill patient.
Targeting ubiquitin-activating enzyme induces ER stress–mediated apoptosis in B-cell lymphoma cells
Authors: Best Scott , Hashiguchi Taylor , Kittai Adam , Bruss Nur , Paiva Cody , Okada Craig , Liu Tingting , Berger Allison , Danilov Alexey V.
Published: January 2019

Alterations in the ubiquitin proteasome system (UPS) leave malignant cells in heightened cellular stress, making them susceptible to proteasome inhibition. However, given the limited efficacy of proteasome inhibitors in non-Hodgkin lymphoma (NHL), novel approaches to target the UPS are needed. Here, we show that TAK-243, the first small-molecule inhibitor of the ubiquitin activating enzyme (UAE) to enter clinical development, disrupts all ubiquitin signaling and global protein ubiquitination in diffuse large B-cell lymphoma (DLBCL) cells, thereby inducing endoplasmic reticulum (ER) stress and the unfolded protein response (UPR). Activation of the ER stress response protein kinase R (PKR)–like ER kinase and phosphorylation of eukaryotic translation initiator factor 2α led to upregulation of the proapoptotic molecule C/EBP homologous protein and cell death across a panel of DLBCL cell lines independent of cell of origin. Concurrently, targeting UAE led to accumulation of Cdt1, a replication licensing factor, leading to DNA rereplication, checkpoint activation, and cell cycle arrest. MYC oncoprotein sensitized DLBCL cells to UAE inhibition; engineered expression of MYC enhanced while genetic MYC knockdown protected from TAK-243–induced apoptosis. UAE inhibition demonstrated enhanced ER stress and UPR and increased potency compared with bortezomib in DLBCL cell lines. In vivo treatment with TAK-243 restricted the growth of xenografted DLBCL tumors, accompanied by reduced cell proliferation and apoptosis. Finally, primary patient-derived DLBCL cells, including those expressing aberrant MYC, demonstrated susceptibility to UAE inhibition. In sum, targeting UAE may hold promise as a novel therapeutic approach in NHL.
Shikonin inhibits cancer cell cycling by targeting Cdc25s
Authors: Zhang Shoude , Gao Qiang , Li Wei , Zhu Luwei , Shang Qianhan , Feng Shuo , Jia Junmei , Jia Qiangqiang , Shen Shuo , Su Zhanhai
Published: January 2019

Background

Shikonin, a natural naphthoquinone, is abundant in Chinese herb medicine Zicao (purple gromwell) and has a wide range of biological activities, especially for cancer. Shikonin and its analogues have been reported to induce cell-cycle arrest, but target information is still unclear. We hypothesized that shikonin, with a structure similar to that of quinone-type compounds, which are inhibitors of cell division cycle 25 (Cdc25) phosphatases, will have similar effects on Cdc25s. To test this hypothesis, the effects of shikonin on Cdc25s and cell-cycle progression were determined in this paper.

Methods

The in vitro effects of shikonin and its analogues on Cdc25s were detected by fluorometric assay kit. The binding mode between shikonin and Cdc25B was modelled by molecular docking. The dephosphorylating level of cyclin-dependent kinase 1 (CDK1), a natural substrate of Cdc25B, was tested by Western blotting. The effect of shikonin on cell cycle progression was investigated by flow cytometry analysis. We also tested the anti-proliferation activity of shikonin on cancer cell lines by MTT assay. Moreover, in vivo anti-proliferation activity was tested in a mouse xenograft tumour model.

Results

Shikonin and its analogues inhibited recombinant human Cdc25 A, B, and C phosphatase with IC50 values ranging from 2.14 ± 0.21 to 13.45 ± 1.45 μM irreversibly. The molecular modelling results showed that shikonin bound to the inhibitor binding pocket of Cdc25B with a favourable binding mode through hydrophobic interactions and hydrogen bonds. In addition, an accumulation of the tyrosine 15-phosphorylated form of CDK1 was induced by shikonin in a concentration-dependent manner in vitro and in vivo. We also confirmed that shikonin showed an anti-proliferation effect on three cancer cell lines with IC50 values ranging from 6.15 ± 0.46 to 9.56 ± 1.03 μM. Furthermore, shikonin showed a promising anti-proliferation effect on a K562 mouse xenograph tumour model.

Conclusion

In this study, we provide evidence for how shikonin induces cell cycle arrest and functions as a Cdc25s inhibitor. It shows an anti-proliferation effect both in vitro and in vivo by mediating Cdc25s.