bluuebunny/crossref_metadata_2025 huggingface dataset:
Extracardiac approach to functional mitral regurgitation: a cost-effective approach to addressing heart failure
Authors: Padmanabhan Chandrashekar , Jagannathan Raghavan , Talluri Krishna , Raman Jaishankar
Published: March 2017

Background

Heart failure is frequently associated with severely impaired ventricular function and manifests often with functional mitral regurgitation (FMR). This is a complex syndrome that is primarily due to abnormal function of the ventricular muscle in the presence of normal mitral leaflets and annulus. Present surgical treatment options approach the problem through mitral valve annulus and leaflets, rather than ventricular muscle. We developed a concept that provides a ventricular solution to this problem.

Methods

After early proof-of-concept studies with polyester mesh, the BACE (Basal Annuloplasty of the Cardia Externally) device was developed along these lines—an adjustable silicone band that is implanted by means of slim polyester belt loops, and secured at the base of the heart. This device can be adjusted remotely under echocardiographic guidance, by inflating the inbuilt balloons that are connected to subcutaneous ports. Initial evaluation in animals showed long-term device safety. Safety and efficacy studies were performed in patients at 4 centres in India. They all underwent coronary artery bypass graft and implantation of the BACE device to correct mitral regurgitation (MR) on a beating heart.

Results

The animal evaluation included 2 components—a group of animals with severe FMR induced by rapid ventricular pacing with long-term implants to establish safety and efficacy and a group of normal animals implanted in a GLP laboratory to ensure device safety for regulatory purposes. The patient population included 11 patients, with a mean age of 58. The mean presurgical left ventricular ejection fraction was 31.8%. The mean MR grade (3.3±0.6) improved to 0.6±0.5 post-BACE implantation (p<0.05). The mean number of bypass grafts was 2.5. The effective improvement in MR was sustained at 6 months in the patients that had completed that duration of the study. All patients were followed up after surgery clinically and echocardiographically. Heart failure symptoms were reduced in all surviving patients with all of them being in NYHA Class I or II at 1-year follow-up.

Conclusions

Epicardial application and adjustment of the BACE device can be performed safely on a beating heart with effective reduction in FMR and sustained benefit in preventing heart failure progression. This early clinical trial shows encouraging results with this approach. This is the first epicardial device for treatment of FMR that can be remotely adjusted. This capability suggests that correction of MR under echocardiograph guidance is feasible.
American football and other sports injuries may cause migraine/persistent pain decades later and can be treated successfully with electrical twitch-obtaining intramuscular stimulation (ETOIMS)
Authors: Chu J , McNally S , Bruyninckx F , Neuhauser D
Published: March 2017

Introduction

Autonomous twitch elicitation at myofascial trigger points from spondylotic radiculopathies-induced denervation supersensitivity can provide favourable pain relief using electrical twitch-obtaining intramuscular stimulation (ETOIMS).

Aim

To provide objective evidence that ETOIMS is safe and efficacious in migraine and persistent pain management due to decades-old injuries to head and spine from paediatric American football.

Methods and materials

An 83-year-old mildly hypertensive patient with 25-year history of refractory migraine and persistent pain self-selected to regularly receive fee-for-service ETOIMS 2/week over 20 months. He had 180 sessions of ETOIMS. Pain levels, blood pressure (BP) and heart rate/pulse were recorded before and immediately after each treatment alongside highest level of clinically elicitable twitch forces/session, session duration and intervals between treatments. Twitch force grades recorded were from 1 to 5, grade 5 twitch force being strongest.

Results

Initially, there was hypersensitivity to electrical stimulation with low stimulus parameters (500 µs pulse-width, 30 mA stimulus intensity, frequency 1.3 Hz). This resolved with gradual stimulus increments as tolerated during successive treatments. By treatment 27, autonomous twitches were noted. Spearman's correlation coefficients showed that pain levels are negatively related to twitch force, number of treatments, treatment session duration and directly related to BP and heart rate/pulse. Treatment numbers and session durations directly influence twitch force. At end of study, headaches and quality of life improved, hypertension resolved and antihypertensive medication had been discontinued.

Conclusions

Using statistical process control methodology in an individual patient, we showed long-term safety and effectiveness of ETOIMS in simultaneous diagnosis, treatment, prognosis and prevention of migraine and persistent pain in real time obviating necessity for randomised controlled studies.
Defining patient centricity with patients for patients and caregivers: a collaborative endeavour
Authors: Yeoman Guy , Furlong Patricia , Seres Michael , Binder Helena , Chung Helena , Garzya Vincenzo , Jones Rachel RM
Published: March 2017

Background

Patient engagement is an essential aspect in the research/development of biopharmaceutical products and disease management. Improving the lives of patients requires a deep understanding of their medical conditions, experiences, needs and priorities. However, a consistent definition of patient centricity is lacking. A series of initiatives was conducted to define patient centricity and its important principles impacting the biopharmaceutical industry.

Methods

Interviews, questionnaires and literature reviews were conducted involving key stakeholders to initially identify issues of importance to patients, healthcare providers and payers. Subsequently, two identical workshops which included 22 patients/carers created a definition of patient centricity and the healthcare values important to patients/caregivers. Outputs were tested in a validation exercise involving patients in predominantly US (n=470) and European (n=703) patient forums.

Results

Initial research provided deeper understanding of patient needs and key topics of interest that were used to cocreate a definition of patient centricity and 10 associated principles of importance to the biopharmaceutical industry. Wider testing of these outputs among predominantly US/European patient communities confirmed their validity. Patient centricity should be defined as ‘Putting the patient first in an open and sustained engagement of the patient to respectfully and compassionately achieve the best experience and outcome for that person and their family’. Important principles for patients focused on education/information, cocreation, access and transparency.

Conclusions

The development of a consistent definition of patient centricity and its associated principles provides an opportunity for biopharmaceutical companies to adopt and use these as a reference point for consistent patient engagement throughout the product life cycle.
Association between physical activity and body fat percentage, with adjustment for BMI: a large cross-sectional analysis of UK Biobank
Authors: Bradbury Kathryn E , Guo Wenji , Cairns Benjamin J , Armstrong Miranda E G , Key Timothy J
Published: March 2017

Objectives

The objective of this study was to examine if, in the general population, physically active adults have less body fat after taking body mass index (BMI) into account.

Design

A cross-sectional analysis of participants recruited into UK Biobank in 2006–2010.

Setting

UK Biobank assessment centres throughout the UK.

Participants

119 230 men and 140 578 women aged 40–69 years, with complete physical activity information, and without a self-reported long-term illness, disability or infirmity.

Exposures

Physical activity measured as excess metabolic equivalent (MET)-hours per week, estimated from a combination of walking, and moderate and vigorous physical activity. BMI from measured height and weight.

Main outcome measure

Body fat percentage estimated from bioimpedance.

Results

BMI and body fat percentage were highly correlated (r=0.85 in women; r=0.79 in men), and both were inversely associated with physical activity. Compared with <5 excess MET-hours/week at baseline, ≥100 excess MET-hours/week were associated with a 1.1 kg/m2lower BMI (27.1 vs 28.2 kg/m2) and 2.8 percentage points lower body fat (23.4% vs 26.3%) in men, and 2.2 kg/m2lower BMI (25.6 vs 27.7 kg/m2) and 4.0 percentage points lower body fat (33.9% vs 37.9%) in women. For a given BMI, greater physical activity was associated with lower average body fat percentage (for a BMI of 22.5–24.99 kg/m2: 2.0 (95% CI 1.8 to 2.2), percentage points lower body fat in men and 1.8 (95% CI 1.6 to 2.0) percentage points lower body fat in women, comparing ≥100 excess MET-hours per week with <5 excess MET-hours/week).

Conclusions

In this sample of middle-aged adults, drawn from the general population, physical activity was inversely associated with BMI and body fat percentage. For people with the same BMI, those who were more active had a lower body fat percentage.
Use of a computerised decision aid (DA) to inform the decision process on adjuvant chemotherapy in patients with stage II colorectal cancer: development and preliminary evaluation
Authors: Miles A , Chronakis I , Fox J , Mayer A
Published: March 2017

Objectives

To develop a computerised decision aid (DA) to inform the decision process on adjuvant chemotherapy in patients with stage II colorectal cancer, and examine perceived usefulness, acceptability and areas for improvement of the DA.

Design

Mixed methods.

Setting

Single outpatient oncology department in central London.

Participants

Consecutive recruitment of 13 patients with stage II colorectal cancer, 12 of whom completed the study. Inclusion criteria were: age >18 years; complete resection for stage II adenocarcinoma of the colon or rectum; patients within 14–56 days after surgery; no contraindication to adjuvant chemotherapy; able to give written informed consent. Exclusion criterion: previous chemotherapy.

Primary outcomes

Patient perceived usefulness (assessed by the PrepDM questionnaire) and acceptability of the DA.

Results

PrepDM scores, measuring the perceived usefulness of the DA in preparing the patient to communicate with their doctor and make a health decision, were above those reported in other patient groups. Patient acceptability scores were also high; however, interviews showed that there was evidence of a lack of understanding of key information among some patients, in particular their baseline risk of recurrence, the net benefit of combination chemotherapy and the rationale for having chemotherapy when cancer had apparently gone.

Conclusions

Patients found the DA acceptable and useful in supporting their decision about whether or not to have adjuvant chemotherapy. Suggested improvements for the DA include: sequential presentation of treatment options (eg, no treatment vs 1 drug, 1 drug vs 2 drugs) to enhance patient understanding of the difference between combination and single therapy, diagrams to help patients understand the rationale for chemotherapy to prevent a recurrence and inbuilt checks on patient understanding of baseline risk of recurrence and net benefit of chemotherapy.
Perspectives on procedure-based assessments: a thematic analysis of semistructured interviews with 10 UK surgical trainees
Authors: Shalhoub Joseph , Marshall Dominic C , Ippolito Kate
Published: March 2017

Objectives

The introduction of competency-based training has necessitated development and implementation of accompanying mechanisms for assessment. Procedure-based assessments (PBAs) are an example of workplace-based assessments that are used to examine focal competencies in the workplace. The primary objective was to understand surgical trainees' perspective on the value of PBA.

Design

Semistructured interviews with 10 surgical trainees individually interviewed to explore their views. Interviews were audio-recorded and transcribed; following this, they were open and axial coded. Thematic analysis was then performed.

Results

Semistructured interviews yielded several topical and recurring themes. In trainees' experience, the use of PBAs as a summative tool limits their educational value. Trainees reported a lack of support from seniors and variation in the usefulness of the tool based on stage of training. Concerns related to the validity of PBAs for evaluating trainees' performance with reports of ‘gaming’ the system and trainees completing their own assessments. Trainees did identify the significant value of PBAs when used correctly. Benefits included the identification of additional learning opportunities, standardisation of assessment and their role in providing a measure of progress.

Conclusions

The UK surgical trainees interviewed identified both limitations and benefits to PBAs; however, we would argue based on their responses and our experience that their use as a summative tool limits their formative use as an educational opportunity. PBAs should either be used exclusively to support learning or solely as a summative tool; if so, further work is needed to audit, validate and standardise them for this purpose.
Global cardiovascular risk assessment in the primary prevention of cardiovascular disease in adults: systematic review of systematic reviews
Authors: Collins Dylan R J , Tompson Alice C , Onakpoya Igho J , Roberts Nia , Ward Alison M , Heneghan Carl J
Published: March 2017

Objective

To identify, critically appraise and summarise existing systematic reviews on the impact of global cardiovascular risk assessment in the primary prevention of cardiovascular disease (CVD) in adults.

Design

Systematic review of systematic reviews published between January 2005 and October 2016 in The Cochrane Library, EMBASE, MEDLINE or CINAHL databases, and post hoc analysis of primary trials.

Participants, interventions, outcomes

Systematic reviews of interventions involving global cardiovascular risk assessment relative to no formal risk assessment in adults with no history of CVD. The primary outcomes of interest were CVD-related morbidity and mortality and all-cause mortality; secondary outcomes were systolic blood pressure (SBP), cholesterol and smoking.

Results

We identified six systematic reviews of variable but generally of low quality (mean Assessing the Methodological Quality of Systematic Reviews 4.2/11, range 0/11 to 7/11). No studies identified by the systematic reviews reported CVD-related morbidity or mortality or all-cause mortality. Meta-analysis of reported randomised controlled trials (RCTs) showed small reductions in SBP (mean difference (MD) −2.22 mm Hg (95% CI −3.49 to −0.95); I2=66%; n=9; GRADE: very low), total cholesterol (MD −0.11 mmol/L (95% CI −0.20 to −0.02); I2=72%; n=5; GRADE: very low), low-density lipoprotein cholesterol (MD −0.15 mmol/L (95% CI −0.26 to −0.05), I2=47%; n=4; GRADE: very low) and smoking cessation (RR 1.62 (95% CI 1.08 to 2.43); I2=17%; n=7; GRADE: low). The median follow-up time of reported RCTs was 12 months (range 2–36 months).

Conclusions

The quality of existing systematic reviews was generally poor and there is currently no evidence reported in these reviews that the prospective use of global cardiovascular risk assessment translates to reductions in CVD morbidity or mortality. There are reductions in SBP, cholesterol and smoking but they may not be clinically significant given their small effect size and short duration. Resources need to be directed to conduct high-quality systematic reviews focusing on hard patient outcomes, and likely further primary RCTs.

Trial registration number

CRD42015019821.
Designing a physical activity intervention for children with asthma: a qualitative study of the views of healthcare professionals, parents and children with asthma
Authors: Jago Russell , Searle Aidan , Henderson A John , Turner Katrina M
Published: March 2017

Objectives

Qualitative methods were used to examine: (1) the attitudes of health professionals to promoting physical activity for children with asthma; (2) reasons why children with asthma are less active and (3) how a physical activity programme for children with asthma could be designed.

Design

Semistructured interviews were conducted with health professionals, children with asthma and their parents between October 2015 and March 2016. Interviews were transcribed verbatim and thematically analysed.

Setting

Primary and secondary care in Bristol (UK).

Participants

Interviews were held with 8 primary care practitioners (5 general practitioners, 2 nurse practitioners and 1 practice nurse), 9 parent–child dyads (2 fathers, 7 mothers, 6 sons, 3 daughters) of children aged 6–7 who had asthma and 4 secondary care professionals (2 respiratory consultants, 2 specialist nurses).

Results

Health professionals reported that physical activity was beneficial for children with asthma and if managed appropriately, children with asthma could be as active as children without asthma. Current promotion of physical activity for children with asthma was limited and restricted by NHS staff time, access to inhalers at school and a lack of parental knowledge. Potentially important components of a new programme include parental education on the possibilities of activity for children with asthma and the difference between exercise-induced breathlessness and asthma symptoms. Other important elements include how to use inhalers as a preventive measure, coping with exacerbations and practical solutions (such as clearing sputum), managing transitions from warm to cold climates and general symptom control.

Conclusions

There is a need to build on current asthma programmes to increase the support for children with asthma to be physically active. Future programmes could consider working more closely with schools, increasing parental knowledge and providing children with practical support to help be physically active.
Qualitative study to explore the health and well-being impacts on adults providing informal support to female domestic violence survivors
Authors: Gregory Alison , Feder Gene , Taket Ann , Williamson Emma
Published: March 2017

Objectives

Domestic violence (DV) is hazardous to survivors' health, from injuries sustained and from resultant chronic physical and mental health problems. Support from friends and relatives is significant in the lives of DV survivors; research shows associations between positive support and the health, well-being and safety of survivors. Little is known about how people close to survivors are impacted. The aim of this study was exploratory, with the following research question: what are the health and well-being impacts on adults who provide informal support to female DV survivors?

Design

A qualitative study using semistructured interviews conducted face to face, by telephone or using Skype. A thematic analysis of the narratives was carried out.

Setting

Community-based, across the UK.

Participants

People were eligible to take part if they had had a close relationship (either as friend, colleague or family member) with a woman who had experienced DV, and were aged 16 or over during the time they knew the survivor. Participants were recruited via posters in community venues, social media and radio advertisement. 23 participants were recruited and interviewed; the majority were women, most were white and ages ranged from mid-20s to 80.

Results

Generated themes included: negative impacts on psychological and emotional well-being of informal supporters, and related physical health impacts. Some psychological impacts were over a limited period; others were chronic and had the potential to be severe and enduring. The impacts described suggested that those providing informal support to survivors may be experiencing secondary traumatic stress as they journey alongside the survivor.

Conclusions

Friends and relatives of DV survivors experience substantial impact on their own health and well-being. There are no direct services to support this group. These findings have practical and policy implications, so that the needs of informal supporters are legitimised and met.
Suppression of interferon-mediated anti-HBV response by single CpG methylation in the 5′-UTR of TRIM22
Authors: Lim Keo-Heun , Park Eun-Sook , Kim Doo Hyun , Cho Kyung Cho , Kim Kwang Pyo , Park Yong Kwang , Ahn Sung Hyun , Park Seung Hwa , Kim Kee-Hwan , Kim Chang Wook , Kang Hong Seok , Lee Ah Ram , Park Soree , Sim Heewoo , Won Juhee , Seok Kieun , You Jueng Soo , Lee Jeong-Hoon , Yi Nam-Joon , Lee Kwang-Woong , Suh Kyung-Suk , Seong Baik L , Kim Kyun-Hwan
Published: March 2017

Objective

Interferons (IFNs) mediate direct antiviral activity. They play a crucial role in the early host immune response against viral infections. However, IFN therapy for HBV infection is less effective than for other viral infections.

Design

We explored the cellular targets of HBV in response to IFNs using proteome-wide screening.

Results

Using LC-MS/MS, we identified proteins downregulated and upregulated by IFN treatment in HBV X protein (HBx)-stable and control cells. We found several IFN-stimulated genes downregulated by HBx, including TRIM22, which is known as an antiretroviral protein. We demonstrated that HBx suppresses the transcription of TRIM22 through a single CpG methylation in its 5′-UTR, which further reduces the IFN regulatory factor-1 binding affinity, thereby suppressing the IFN-stimulated induction of TRIM22.

Conclusions

We verified our findings using a mouse model, primary human hepatocytes and human liver tissues. Our data elucidate a mechanism by which HBV evades the host innate immune system.
The effect of excise tax increases on cigarette prices in South Africa
Authors: Linegar Daniel J , van Walbeek Corne
Published: March 2017

Introduction

The effectiveness of excise tax increases as a tool for reducing tobacco consumption depends largely on how the tax increases impact the retail price. We estimate this relationship in South Africa for 2001–2015.

Data

Statistics South Africa provided disaggregated cigarette price data, used in the calculation of the Consumers’ Price Index. Data on the excise tax per cigarette were obtained from Budget Reviews prepared by the National Treasury of South Africa.

Methods

Regression equations were estimated for each month. The month-on-month change in cigarette prices in February through April was regressed against March’s excise tax change to estimate the pass-through coefficient. For the other 9 months, the month-on-month change in cigarette price was regressed against monthly dummy variables to determine the size of the non-tax-related price increase in each of these months. The analysis was performed in both nominal and real (inflation-adjusted) terms.

Findings

Expressed in real terms, the excise tax was undershifted. A R1.00 (one rand) increase in the excise tax is associated with an increase in the retail price of cigarettes of R0.90 in the pre-2010 period, and R0.49 in the post-2010 period. In the pre-2010 period, the tobacco industry increased the retail price of cigarettes in July/August, independent of the excise tax increase. The discretionary July/August price increases largely disappeared after 2010, primarily because the market became more competitive.

Conclusion

The degree of excise tax pass-through, and the magnitude of discretionary increases in cigarette prices, is significantly determined by the competitive environment in the cigarette market.
Sciatic and femoral nerve blockade using bupivacaine alone, or in combination with dexmedetomidine or buprenorphine in cats
Authors: Evangelista M. C. , Doodnaught G. M. , Fantoni D. T. , Steagall P. V. M.
Published: March 2017

The aim of this study was to determine the onset and offset of antinociception after sciatic (ScN) and femoral (FN) nerve blocks. Six healthy adult cats (4.8±1.3years; 4.3±0.4 kg) were included in a randomised, crossover, blinded and controlled study. Following sedation with dexmedetomidine (25 µg/kg, intramuscular), each ScN and FN injection was performed using 0.1 ml/kg of saline (CONTROL), bupivacaine (0.46 per cent, 0.46 mg/kg; BUPI), bupivacaine and dexmedetomidine (1 µg/kg; BUPI‐DEX) or bupivacaine and buprenorphine (2.5 µg/kg; BUPI‐BUPRE). Atipamezole (250 µg/kg) was administered after injections. Paw withdrawal thresholds (PWT) and motor blockade were evaluated before sedation and up to 24 hours. The PWT were significantly increased at half an hour in CONTROL, from two to four hours in BUPI and BUPI‐DEX when compared with baseline. Motor blockade was observed between one and three hours in treatments using bupivacaine. Ability to walk was significantly impaired in BUPI at half an hour to two hours, BUPI‐DEX at one to two hours and BUPI‐BUPRE at two hours. Antinociception was observed in BUPI between one and eight hours, and in BUPI‐DEX and BUPI‐BUPRE between one and four hours. This study could not demonstrate a benefit of administering bupivacaine with dexmedetomidine or buprenorphine in cats. Results in BUPI‐DEX may have been biased by the administration of atipamezole.
Supervisor descriptions of veterinary student performance in the clinical workplace: a qualitative interview study
Authors: Norman E. J.
Published: March 2017

This qualitative study investigated the qualities of veterinary student performance that inform a supervisor's impression of their competency. Semi‐structured interviews were conducted with a purposive sample of 15 supervisors from different veterinary subdisciplines, to elicit descriptions of excellent, weak and marginal students. Thematic analysis of transcriptions revealed 12 themes, of which engagement was frequently discussed and of stated importance, and trustworthiness was a differentiator of weak and marginal students from excellent students. Other themes were knowledge, application of knowledge, technical and animal handling skills, communication, social interaction, personal functioning, caring for animals, impact, prospects and the difficulty in judging competency. Patterns of association of themes were found, however themes were also used independently in unique combinations for most students described. The findings show the range of abilities, behaviours, attitudes and personal characteristics of students that are considered by supervisors and how these are weighted and balanced. The key contribution of engagement and trustworthiness to the overall impression aligns with research indicating their importance for success in clinical practice, as both contributors to competency and indicators of it. The findings may inform future design and investigation of workplace‐based learning and in‐training evaluation, as well as conceptions of veterinary competency.
Behaviour of slate following freeze–thaw and dry–wet weathering processes
Authors: Cui Kai , Wu Guopeng , Wang Xiuli , Chen Wenwu
Published: March 2017

The regions of Zhouqu and Wudu in Gansu Province, China, experience some of the world's most severe debris-flow-related disasters, such as landslides and mudslides. The intensity of these events is attributed to the underlying Silurian slate lithology, which undergoes freeze–thaw and dry–wet weathering processes. In addition, the regional climate allows these processes to alternate, which intensifies the weathering of the slate. In this study, the physical weathering of slate was assessed using photographs and measurement of variations in characteristics such as quality, elastic velocity, stress–strain curves and uniaxial compressive strength. Varying numbers of cycles of either freeze–thaw or dry–wet weathering processes, or an alternating combination of the two cycles, were applied to samples. Rules defining the correlative index of slate weathering were established via correlation regression and fitting analyses. Variations in physical and mechanical properties in response to weathering were used to elucidate the weathering and behavioural mechanisms of the slate under the different weathering processes. The results also provided a reference for both evaluating slope stability and predicting the potential for debris-flow disasters within the study region.
Microvascular leakage in acute myocardial infarction: characterization by histology, biochemistry, and magnetic resonance imaging
Authors: Gao Xiao-Ming , Wu Qi-Zhu , Kiriazis Helen , Su Yidan , Han Li-Ping , Pearson James Todd , Taylor Andrew J. , Du Xiao-Jun
Published: March 2017

Cardiac microvascular obstruction (MVO) after ischemia-reperfusion (I/R) has been well studied, but microvascular leakage (MVL) remains largely unexplored. We characterized MVL in the mouse I/R model by histology, biochemistry, and cardiac magnetic resonance (CMR) imaging. I/R was induced surgically in mice. MVL was determined by administrating the microvascular permeability tracer Evans blue (EB) and/or gadolinium-diethylenetriaminepentaacetic acid contrast. The size of MVL, infarction, and MVO in the heart was quantified histologically. Myocardial EB was extracted and quantified chromatographically. Serial CMR images were acquired from euthanized mice to determine late gadolinium enhancement (LGE) for comparison with MVL quantified by histology. I/R resulted in MVL with its severity dependent on the ischemic duration and reaching its maximum at 24–48 h after reperfusion. The size of MVL correlated with the degree of left ventricular dilatation and reduction in ejection fraction. Within the risk zone, the area of MVL (75 ± 2%) was greater than that of infarct (47 ± 4%, P < 0.01) or MVO (36 ± 4%, P < 0.01). Contour analysis of paired CMR-LGE by CMR and histological MVL images revealed a high degree of spatial colocalization ( r = 0.959, P < 0.0001). These data indicate that microvascular barrier function is damaged after I/R leading to MVL. Histological and biochemical means are able to characterize MVL by size and severity while CMR-LGE is a potential diagnostic tool for MVL. The size of ischemic myocardium exhibiting MVL was greater than that of infarction and MVO, implying a role of MVL in postinfarct pathophysiology.

NEW & NOTEWORTHY We characterized, for the first time, the features of microvascular leakage (MVL) as a consequence of reperfused myocardial infarction. The size of ischemic myocardium exhibiting MVL was significantly greater than that of infarction or no reflow. We made a proof-of-concept finding on the diagnostic potential of MVL by cardiac magnetic resonance imaging.
Sept7bis required for the subcellular organization of cardiomyocytes and cardiac function in zebrafish
Authors: Dash Surjya Narayan , Narumanchi Suneeta , Paavola Jere , Perttunen Sanni , Wang Hong , Lakkisto Päivi , Tikkanen Ilkka , Lehtonen Sanna
Published: March 2017

Myofibrils made up of actin, myosin, and associated proteins generate the contractile force in muscle, and, consequently, mutations in these proteins may lead to heart failure. Septins are a conserved family of small GTPases that associate with actin filaments, microtubules, and cellular membranes. Despite the importance of septins in cytoskeleton organization, their role in cardiomyocyte organization and function is poorly characterized. Here, we show that septin 7 is expressed in both embryonic and adult zebrafish hearts and elucidate the physiological significance of sept7b, the zebrafish ortholog of human septin 7, in the heart in embryonic and larval zebrafish. Knockdown of sept7b reduced F-actin and α-cardiac actin expression in the heart and caused disorganization of actin filaments. Electron microscopy of sept7b-depleted larvae showed disorganization of heart myofibrils and partial detachment from Z-disks. Functional studies revealed that knockdown of sept7b leads to reduced ventricular dimensions, contractility, and cardiac output. Furthermore, we found that depletion of sept7b diminished the expression of retinaldehyde dehydrogenase 2, which catalyzes the synthesis of retinoic acid necessary for heart morphogenesis. We further observed that the sept7b and retinoic acid signaling pathways converge to regulate cardiac function. Together, these results specify an essential role for sept7b in the contractile function of the heart.

NEW & NOTEWORTHY Knockdown of the zebrafish ortholog of human septin 7 ( sept7b) destabilizes cardiac actin and reduces ventricular dimensions, contractility, and cardiac output in larval zebrafish, indicating that sept7b is essential for cardiac function. We further found that sept7b and retinoic acid signaling pathways converge to regulate cardiac function. These data prompt further studies defining the role of sept7b in cardiomyopathies.
Elevated Serum Levels of sCD30 and IL6 and Detectable IL10 Precede Classical Hodgkin Lymphoma Diagnosis
Authors: Levin Lynn I. , Breen Elizabeth C. , Birmann Brenda M. , Batista Julie L. , Magpantay Larry I. , Li Yuanzhang , Ambinder Richard F. , Mueller Nancy E. , Martínez-Maza Otoniel
Published: March 2017

Background: We investigated whether an immune system environment characterized by elevated serum levels of B-cell activation molecules was associated with the subsequent development of classical Hodgkin lymphoma (cHL).

Methods: We measured serum levels of B-cell–stimulatory cytokines, IL6 and IL10, soluble CD30 (sCD30), and total IgE prior to cHL diagnosis in 103 cases and 206 matched controls with archived specimens in the DoD Serum Repository.

Results: Prediagnosis serum sCD30 and IL6 levels had strong positive associations with risk of a cHL diagnosis 0 to 1 year prior to diagnosis [sCD30 OR = 5.5; 95% confidence interval (CI), 3.4–9.0; IL6 OR = 4.6; 95% CI, 2.9–7.5] and >1 year to 2 years pre-cHL diagnosis (sCD30 OR = 3.3; 95% CI, 1.6–6.7; IL6 OR = 2.9; 95% CI, 1.3–6.5). We observed similar, albeit not consistently significant positive associations, over 4 or more years preceding diagnosis. We did not observe a clear association with IgE levels. Of note, detectable IL10 levels were significantly associated with Epstein–Barr virus (EBV)-positive cHL cases compared with EBV-negative cases.

Conclusion: In this prospective analysis, elevated sCD30 and IL6 levels and detectable IL10 preceded cHL diagnosis.

Impact: The associations of these cytokines with cHL risk may reflect the production of these molecules by proliferating nascent cHL tumor cells, or by immune cells responding to their presence, prior to clinical detection. The stable elevation in cHL risk, 4 or more years prediagnosis, also suggests that a B-cell–stimulatory immune system milieu precedes, and may promote, lymphomagenesis. Cancer Epidemiol Biomarkers Prev; 26(7); 1114–23. ©2017 AACR.
High Salt Intake Is Associated with Atrophic Gastritis with Intestinal Metaplasia
Authors: Song Ji Hyun , Kim Young Sun , Heo Nam Ju , Lim Joo Hyun , Yang Sun Young , Chung Goh Eun , Kim Joo Sung
Published: March 2017

Background: Although several studies have investigated excessive salt intake as a risk factor for gastric precancerous lesions, such as atrophic gastritis and intestinal metaplasia, the evidence is insufficient to make a conclusion. We evaluated the association between gastric precancerous lesions and salt intake.

Methods: From 2008 to 2015, the medical records of 728 subjects who underwent upper gastrointestinal endoscopy and sodium excretion in 24-hour urine tests were retrospectively reviewed. Sixty-six subjects were excluded due to diuretics use (n = 55), diagnosis with a gastric neoplasm (n = 4), or the cases of intestinal metaplasia in the absence of atrophy (n = 7), so 662 subjects were included. Atrophic gastritis and intestinal metaplasia were diagnosed by endoscopic findings. The subjects were grouped into three levels by tertiles of 24-hour urine sodium excretion.

Results: A total of 192 (29.0%) had atrophic gastritis without intestinal metaplasia and 112 (16.9%) had atrophic gastritis with intestinal metaplasia. A total of 276 subjects (61.5%) were infected with Helicobacter pylori (H. pylori). In multivariate analyses, H. pylori infection [OR = 14.17; 95% confidence interval (CI), 7.12–28.22) was associated with atrophic gastritis without intestinal metaplasia. Highest levels of sodium excretion (OR = 2.870; 95% CI, 1.34–6.14), heavy smoking (≥20 pack-years) (OR = 2.75; 95% CI, 1.02–7.39), and H. pylori infection (OR = 3.96; 95% CI, 2.02–7.76) were associated with atrophic gastritis with intestinal metaplasia.

Conclusions: Our endoscopy-based study suggested that high salt intake could be associated with an increased risk of atrophic gastritis with intestinal metaplasia.

Impact: Low salt diet might be helpful to prevent gastric carcinogenesis. Cancer Epidemiol Biomarkers Prev; 26(7); 1133–8. ©2017 AACR.
The Promise of Targeting Macrophages in Cancer Therapy
Authors: Brown J. Martin , Recht Lawrence , Strober Samuel
Published: March 2017

Cancer therapy has developed around the concept of killing, or stopping the growth of, the cancer cells. Molecularly targeted therapy is the modern expression of this paradigm. Increasingly, however, the realization that the cancer has co-opted the normal cells of the stroma for its own survival has led to the concept that the tumor microenvironment (TME) could be targeted for effective therapy. In this review, we outline the importance of tumor-associated macrophages (TAM), a major component of the TME, in the response of tumors to cancer therapy. We discuss the normal role of macrophages in wound healing, the major phenotypes of TAMs, and their role in blunting the efficacy of cancer treatment by radiation and anticancer drugs, both by promoting tumor angiogenesis and by suppressing antitumor immunity. Finally, we review the many preclinical studies that have shown that the response of tumors to irradiation and anticancer drugs can be improved, sometimes markedly so, by depleting TAMs from tumors or by suppressing their polarization from an M1 to an M2 phenotype. The data clearly support the validity of clinical testing of combining targeting TAMs with conventional therapy. Clin Cancer Res; 23(13); 3241–50. ©2017 AACR.
Discovery and Pharmacological Characterization of JNJ-42756493 (Erdafitinib), a Functionally Selective Small-Molecule FGFR Family Inhibitor
Authors: Perera Timothy P.S. , Jovcheva Eleonora , Mevellec Laurence , Vialard Jorge , De Lange Desiree , Verhulst Tinne , Paulussen Caroline , Van De Ven Kelly , King Peter , Freyne Eddy , Rees David C. , Squires Matthew , Saxty Gordon , Page Martin , Murray Christopher W. , Gilissen Ron , Ward George , Thompson Neil T. , Newell David R. , Cheng Na , Xie Liang , Yang Jennifer , Platero Suso J. , Karkera Jayaprakash D. , Moy Christopher , Angibaud Patrick , Laquerre Sylvie , Lorenzi Matthew V.
Published: March 2017

Fibroblast growth factor (FGF) signaling plays critical roles in key biological processes ranging from embryogenesis to wound healing and has strong links to several hallmarks of cancer. Genetic alterations in FGF receptor (FGFR) family members are associated with increased tumor growth, metastasis, angiogenesis, and decreased survival. JNJ-42756493, erdafitinib, is an orally active small molecule with potent tyrosine kinase inhibitory activity against all four FGFR family members and selectivity versus other highly related kinases. JNJ-42756493 shows rapid uptake into the lysosomal compartment of cells in culture, which is associated with prolonged inhibition of FGFR signaling, possibly due to sustained release of the inhibitor. In xenografts from human tumor cell lines or patient-derived tumor tissue with activating FGFR alterations, JNJ-42756493 administration results in potent and dose-dependent antitumor activity accompanied by pharmacodynamic modulation of phospho-FGFR and phospho-ERK in tumors. The results of the current study provide a strong rationale for the clinical investigation of JNJ-42756493 in patients with tumors harboring FGFR pathway alterations. Mol Cancer Ther; 16(6); 1010–20. ©2017 AACR.
Tumor-Associated Macrophages Can Contribute to Antitumor Activity through FcγR-Mediated Processing of Antibody–Drug Conjugates
Authors: Li Fu , Ulrich Michelle , Jonas Mechthild , Stone Ivan J. , Linares Germein , Zhang Xinqun , Westendorf Lori , Benjamin Dennis R. , Law Che-Leung
Published: March 2017

The primary mechanism of antibody–drug conjugates (ADC) is targeted delivery of a cytotoxic payload to tumor cells via cancer-associated membrane receptors. However, the tumor microenvironment likely plays a role in ADC penetration, distribution, and processing and thus impacts the overall antitumor activity. Here, we report on the potential contribution of Fc–FcγR interactions between ADCs and tumor-associated macrophages (TAM) to the preclinical antitumor activities of ADCs. In the CD30+ L-428 Hodgkin lymphoma model, anti-CD30-vcMMAE and a non-binding control (hIgG-vcMMAE) demonstrated similar antitumor activity as well as similar payload release in the tumors. IHC analysis revealed L-428 tumors contained highly abundant TAMs, which were confirmed to bind ADCs by IHC and flow cytometry. The infiltration of TAMs was further found to correlate with the antitumor activity of the non-binding hIgG-vcMMAE in five additional xenograft models. hIgG1V1-vcMMAE, bearing a mutation in the Fc region which ablates Fc gamma receptor (FcγR) binding, lost antitumor activity in three TAM-high xenograft models, suggesting Fc–FcγR interactions modulate the TAM-ADC interaction. Our results suggest that TAMs can contribute to ADC processing through FcγR interaction in preclinical tumor models and may represent an important additional mechanism for drug release from ADCs. Correlative studies in clinical trials will further shed light on whether TAMs play a role in patients' response to ADC therapies. Mol Cancer Ther; 16(7); 1347–54. ©2017 AACR.
Genotype-Phenotype Correlation of
SCN5A
Mutation for the Clinical and Electrocardiographic Characteristics of Probands With Brugada Syndrome
Authors: Yamagata Kenichiro , Horie Minoru , Aiba Takeshi , Ogawa Satoshi , Aizawa Yoshifusa , Ohe Tohru , Yamagishi Masakazu , Makita Naomasa , Sakurada Harumizu , Tanaka Toshihiro , Shimizu Akihiko , Hagiwara Nobuhisa , Kishi Ryoji , Nakano Yukiko , Takagi Masahiko , Makiyama Takeru , Ohno Seiko , Fukuda Keiichi , Watanabe Hiroshi , Morita Hiroshi , Hayashi Kenshi , Kusano Kengo , Kamakura Shiro , Yasuda Satoshi , Ogawa Hisao , Miyamoto Yoshihiro , Kapplinger Jamie D. , Ackerman Michael J. , Shimizu Wataru
Published: March 2017

Background:

The genotype-phenotype correlation of
SCN5A
mutations as a predictor of cardiac events in Brugada syndrome remains controversial. We aimed to establish a registry limited to probands, with a long follow-up period, so that the genotype-phenotype correlation of
SCN5A
mutations in Brugada syndrome can be examined without patient selection bias.

Methods:

This multicenter registry enrolled 415 probands (n=403; men, 97%; age, 46±14 years) diagnosed with Brugada syndrome whose
SCN5A
gene was analyzed for mutations.

Results:

During a mean follow-up period of 72 months, the overall cardiac event rate was 2.5%/y. In comparison with probands without mutations (
SCN5A
(–), n=355), probands with
SCN5A
mutations (
SCN5A
(+), n=60) experienced their first cardiac event at a younger age (34 versus 42 years,
P
=0.013), had a higher positive rate of late potentials (89% versus 73%,
P
=0.016), exhibited longer P-wave, PQ, and QRS durations, and had a higher rate of cardiac events (
P
=0.017 by log-rank). Multivariate analysis indicated that only
SCN5A
mutation and history of aborted cardiac arrest were significant predictors of cardiac events (
SCN5A
(+) versus
SCN5A
(–): hazard ratio, 2.0 and
P
=0.045; history of aborted cardiac arrest versus no such history: hazard ratio, 6.5 and
P
<0.001).

Conclusions:

Brugada syndrome patients with
SCN5A
mutations exhibit more conduction abnormalities on ECG and have higher risk for cardiac events.
An
NPPB
Promoter Polymorphism Associated With Elevated N‐Terminal pro–B‐Type Natriuretic Peptide and Lower Blood Pressure, Hypertension, and Mortality
Authors: Seidelmann Sara B. , Vardeny Orly , Claggett Brian , Yu Bing , Shah Amil M. , Ballantyne Christie M. , Selvin Elizabeth , MacRae Calum A. , Boerwinkle Eric , Solomon Scott D.
Published: March 2017

Background

Elevated B‐type natriuretic peptide (
BNP
) levels are associated with heart failure and increased mortality in the general population. We investigated rs198389, a functional variant in the promoter region of the
BNP
gene (

NPPB

), in patients from the Atherosclerosis Risk in Communities Study to investigate associations with N‐terminal pro‐BNP (NT‐pro
BNP)
levels and outcomes.

Methods and Results

A total of 11 361 black and white patients with rs198389 genotyping attended visit 1 (aged 45–64 years; 1987–1989), with follow‐up visits occurring every 3 years (visit 2–visit 4, 1990–1999), followed by visit 5 (2011–2013).
NT
‐pro
BNP
levels were measured at visits 2, 4, and 5. At visit 2, the
GG
genotype (frequency 18%) was associated with a 41% higher mean plasma level of
NT
‐pro
BNP
compared with the
AA
genotype (frequency 34%), with intermediate values observed in
AG
s (
P
=4.2×10
−52
). The
GG
genotype was associated with reduced systolic blood pressure (−1.6 mm Hg,
P
=0.006), diastolic blood pressure (−1 mm Hg,
P
=0.003), antihypertension medication use (odds ratio, 0.85; 95%
CI
, 0.74–0.97 [
P
=0.02]), and hypertension (odds ratio, 0.81; 95%
CI
, 0.72–0.92 [
P
=0.002]) compared with the
AA
genotype with intermediate values in
AG
s. These relationships persisted throughout subsequent visits. After a median follow‐up of 23 years, there were 4031 deaths. With and without covariate adjustment, the
GG
genotype was associated with modestly lower mortality (hazard ratio, 0.86; 95% CI, 0.78–0.95), primarily reflective of cardiovascular death (hazard ratio, 0.75; 95% CI, 0.61–0.92), and increased residual lifespan of 8 months from 50 years of age (
P
=0.02) versus
AA
s.

Conclusions

The rs198389 G allele in the

NPPB

promoter is associated with elevated levels of
NT
‐pro
BNP
throughout adult life, reduced blood pressure, hypertension and cardiovascular mortality, and increased lifespan.
Proportional Recovery From Lower Limb Motor Impairment After Stroke
Authors: Smith Marie-Claire , Byblow Winston D. , Barber P. Alan , Stinear Cathy M.
Published: March 2017

Background and Purpose—

In people with preserved corticospinal tract (CST) function after stroke, upper limb impairment resolves by ≈70% within 3 months. This is known as the proportional recovery rule. Patients without CST function do not fit this rule and have worse upper limb outcomes. This study investigated resolution of motor impairment in the lower limb (LL).

Methods—

Patients with stroke and LL weakness were assessed 3 days and 3 months after stroke with the LL Fugl–Meyer. CST integrity was determined in a subset of patients using transcranial magnetic stimulation to test for LL motor-evoked potentials and magnetic resonance imaging to measure CST lesion load. Linear regression analyses were conducted to predict resolution of motor impairment (ΔFugl–Meyer) including factors initial impairment, motor-evoked potential status, CST lesion load, and LL therapy dose.

Results—

Thirty-two patients completed 3-month follow-up and recovered 74% (95% confidence interval, 60%–88%) of initial LL motor impairment. Initial impairment was the only significant predictor of resolution of motor impairment. There was no identifiable cluster of patients who did not fit the proportional recovery rule. Measures of CST integrity did not predict proportional LL recovery.

Conclusions—

LL impairment resolves by ≈70% within 3 months after stroke. The absence of a nonfitter group may be because of differences in the neuroanatomical organization of descending motor tracts to the upper limb and LL. Proportional recovery of the LL is not influenced by therapy dose providing further evidence that it reflects a fundamental biological process.