bluuebunny/crossref_metadata_2025 huggingface dataset:
Comorbidities, complications and mortality in people of South Asian ethnicity with type 1 diabetes compared with other ethnic groups: a systematic review
Authors: Sarwar Komil N , Cliff Phoebe , Saravanan Ponnusamy , Khunti Kamlesh , Nirantharakumar Krishnarajah , Narendran Parth
Published: July 2017

Objective

The aim of this systematic review is to explore the association of South Asian (SA) ethnicity on comorbidities, microvascular and macrovascular complications and mortality compared with other ethnic groups in people with type 1 diabetes mellitus (T1DM).

Design

Systematic review.

Method

A systematic literature search strategy was designed and carried out using Medline and Embase for full-text and abstract studies published in English from 1946 to February 2016. The initial search identified 4722 papers. We assessed 305 full-text articles in detail for potential inclusion. Ten papers met the inclusion criteria for review and an additional one paper was included from our secondary search strategy using the bibliography of included studies. In total, 11 studies were included.

Eligibility criteria for selecting studies

Studies were included if they were published in English, involved SA participants with T1DM and compared them with non-SA participants and assessed one of the outcomes of comorbidities, microvascular complications, macrovascular complications and mortality.

Results

SA with T1DM have higher mortality compared with white Europeans (WE), mainly contributed to by excess cardiovascular disease. SA have significantly higher glycated haemoglobin (HbA1c), lower high-density lipoprotein (HDL) and lower rates of neuropathy compared with WE. There were no differences in rates of retinopathy and nephropathy. Compared with Africans, SA had lower levels of microalbuminuria, HbA1c and systolic blood pressure and higher HDL levels. There were no significant differences in the remaining outcomes: cardiovascular disease, retinopathy, neuropathy and body mass index. Furthermore, SA have higher HbA1c levels than Malay and Chinese and higher waistâ€“hip ratio and lower HDL levels compared with Chinese only.

Conclusion

Our analysis highlights ethnic disparity in macrovascular outcomes that is so evident for type 2 diabetes mellitus may also be present for SA patients with T1DM. We highlight the need for a large, prospective, cohort study exploring the effect of ethnicity in a uniform healthcare setting.
Occupational risk forLegionellainfection among dental healthcare workers: meta-analysis in occupational epidemiology
Authors: Petti Stefano , Vitali Matteo
Published: July 2017

Objective

The occupational risk forLegionellainfection among dental healthcare workers (DHCWs) is conjectured because of the risk of routine inhalation of potentially contaminated aerosols produced by the dental instruments. Nevertheless, occupational epidemiology studies are contrasting. This meta-analysis assessed the level of scientific evidence regarding the relative occupational risk forLegionellainfection among DHCWs.

Methods

Literature search was performed without time and language restrictions, using broad data banks (PubMed, Scopus, Web of Science, GOOGLE Scholar) and generic keywords (‘legionella’ AND ‘dent*’). Analytical cross-sectional studies comparing prevalence of high serumLegionellaantibody levels in DHCWs and occupationally unexposed individuals were considered. The relative occupational risk was assessed through prevalence ratio (PR) with 95% CI. Between-study heterogeneity was assessed (Cochran’s Q test) and was used to choose the meta-analytic method. Study quality (modified Newcastle-Ottawa Scale) and publication bias (Begg and Mazumdar’s test, Egger and colleagues’ test, trim and fill R0method) were assessed formally and considered for the sensitivity analysis. Sensitivity analysis to study inclusion, subgroup analyses (dental staff categories; publication year, before vs after 1998, ie, 5 years after the release by the Centers for Disease Control and Prevention of the infection control guidelines in dental healthcare setting) were performed.

Results

Seven studies were included (2232 DHCWs, 1172 occupationally unexposed individuals). No evidence of publication bias was detected. The pooled PR estimate was statistically non-significant at 95% level (1.7; 95% CI 0.8 to 3.2), study-quality adjustment did not change the PR considerably (PR, 1.5; 95% CI 0.5 to 4.1). PR was statistically significant before 1998 and no longer significant after 1998. Subgroup analysis according to DHCW categories was inconclusive.

Conclusions

There is no scientific evidence that DHCWs are at high occupational risk. The differences between former and recent studies could be due to different characteristics of municipal water systems and the infection control guideline dissemination.
A study protocol for an observational cohort investigating COGnitive outcomes and WELLness in survivors of critical illness: the COGWELL study
Authors: Wilcox M Elizabeth , Lim Andrew S , McAndrews Mary P , Wennberg Richard A , Pinto Ruxandra L , Black Sandra E , Walczak Karolina D , Friedrich Jan O , Taglione Michael S , Rubenfeld Gordon D
Published: July 2017

Introduction

Up to 9 out of 10 intensive care unit (ICU) survivors will suffer some degree of cognitive impairment at hospital discharge and approximately half will have decrements that persist for years. The mechanisms for this newly acquired brain injury are poorly understood. The purpose of this study is to describe the prevalence of sleep abnormalities and their association with cognitive impairment, examine a well-known genetic risk factor for dementia (Apolipoprotein E ε4) that may allow for genetic risk stratification of ICU survivors at greatest risk of cognitive impairment and determine if electroencephalography (EEG) is an independent predictor of long-term cognitive impairment and possibly a candidate intermediate end point for future clinical trials.

Methods and analysis

This is a multisite, prospective, observational cohort study. The setting for this trial will be medical and surgical ICUs of five large tertiary care referral centres. The participants will be adult patients admitted to a study ICU and invasively ventilated for ≥3 days . Participants will undergo follow-up within 7 days of ICU discharge, 6 months and 1 year. At each time point, patients will have an EEG, blood work (biomarkers; gene studies), sleep study (actigraphy), complete a number of questionnaires as well as undergo neuropsychological testing. The primary outcome of this study will be long-term cognitive function at 12 months follow-up as measured by the Repeatable Battery for the Assessment of Neuropsychological Status and Trails Making Test B.

Ethics and dissemination

The study has received the following approvals: University Health Network Research Ethics Committee (13–6425-BE), Sunnybrook Health Centre Research Ethics Committee (365–2013), Mount Sinai Research Ethics Committee (14–0194-E) and St. Michael’s Hospital Research Ethics Committee (14-295). Results will be made available to critical care survivors, their caregivers, the funders, the critical care societies and other researchers.

Trial registration number

NCT02086877; Pre-results.
Trends in readmission rates for safety net hospitals and non-safety net hospitals in the era of the US Hospital Readmission Reduction Program: a retrospective time series analysis using Medicare administrative claims data from 2008 to 2015
Authors: Salerno Amy M , Horwitz Leora I , Kwon Ji Young , Herrin Jeph , Grady Jacqueline N , Lin Zhenqiu , Ross Joseph S , Bernheim Susannah M
Published: July 2017

Objective

To compare trends in readmission rates among safety net and non-safety net hospitals under the US Hospital Readmission Reduction Program (HRRP).

Design

A retrospective time series analysis using Medicare administrative claims data from January 2008 to June 2015.

Setting

We examined 3254 US hospitals eligible for penalties under the HRRP, categorised as safety net or non-safety net hospitals based on the hospital’s proportion of patients with low socioeconomic status.

Participants

Admissions for Medicare fee-for-service patients, age ≥65 years, discharged alive, who had a valid five-digit zip code and did not have a principal discharge diagnosis of cancer or psychiatric illness were included, for a total of 52 516 213 index admissions.

Primary and secondary outcome measures

Mean hospital-level, all-condition, 30-day risk-adjusted standardised unplanned readmission rate, measured quarterly, along with quarterly rate of change, and an interrupted time series examining: April–June 2010, after HRRP was passed, and October–December 2012, after HRRP penalties were implemented.

Results

58.0% (SD 15.3) of safety net hospitals and 17.1% (SD 10.4) of non-safety net hospitals’ patients were in the lowest quartile of socioeconomic status. The mean safety net hospital standardised readmission rate declined from 17.0% (SD 3.7) to 13.6% (SD 3.6), whereas the mean non-safety net hospital declined from 15.4% (SD 3.0) to 12.7% (SD 2.5). The absolute difference in rates between safety net and non-safety net hospitals declined from 1.6% (95% CI 1.3 to 1.9) to 0.9% (0.7 to 1.2). The quarterly decline in standardised readmission rates was 0.03 percentage points (95% CI 0.03 to 0.02, p<0.001) greater among safety net hospitals over the entire study period, and no differential change among safety net and non-safety net hospitals was found after either HRRP was passed or penalties enacted.

Conclusions

Since HRRP was passed and penalties implemented, readmission rates for safety net hospitals have decreased more rapidly than those for non-safety net hospitals.
A developmental evaluation to enhance stakeholder engagement in a wide-scale interactive project disseminating quality improvement data: study protocol for a mixed-methods study
Authors: Laycock Alison , Bailie Jodie , Matthews Veronica , Cunningham Frances , Harvey Gillian , Percival Nikki , Bailie Ross
Published: July 2017

Introduction

Bringing together continuous quality improvement (CQI) data from multiple health services offers opportunities to identify common improvement priorities and to develop interventions at various system levels to achieve large-scale improvement in care. An important principle of CQI is practitioner participation in interpreting data and planning evidence-based change. This study will contribute knowledge about engaging diverse stakeholders in collaborative and theoretically informed processes to identify and address priority evidence-practice gaps in care delivery. This paper describes a developmental evaluation to support and refine a novel interactive dissemination project using aggregated CQI data from Aboriginal and Torres Strait Islander primary healthcare centres in Australia. The project aims to effect multilevel system improvement in Aboriginal and Torres Strait Islander primary healthcare.

Methods and analysis

Data will be gathered using document analysis, online surveys, interviews with participants and iterative analytical processes with the research team. These methods will enable real-time feedback to guide refinements to the design, reports, tools and processes as the interactive dissemination project is implemented. Qualitative data from interviews and surveys will be analysed and interpreted to provide in-depth understanding of factors that influence engagement and stakeholder perspectives about use of the aggregated data and generated improvement strategies. Sources of data will be triangulated to build up a comprehensive, contextualised perspective and integrated understanding of the project's development, implementation and findings.

Ethics and dissemination

The Human Research Ethics Committee (HREC) of the Northern Territory Department of Health and Menzies School of Health Research (Project 2015-2329), the Central Australian HREC (Project 15-288) and the Charles Darwin University HREC (Project H15030) approved the study. Dissemination will include articles in peer-reviewed journals, policy and research briefs. Results will be presented at conferences and quality improvement network meetings. Researchers, clinicians, policymakers and managers developing evidence-based system and policy interventions should benefit from this research.
Assessing the effectiveness of a 3-month day-and-night home closed-loop control combined with pump suspend feature compared with sensor-augmented pump therapy in youths and adults with suboptimally controlled type 1 diabetes: a randomised parallel study protocol
Authors: Bally Lia , Thabit Hood , Tauschmann Martin , Allen Janet M , Hartnell Sara , Wilinska Malgorzata E , Exall Jane , Huegel Viki , Sibayan Judy , Borgman Sarah , Cheng Peiyao , Blackburn Maxine , Lawton Julia , Elleri Daniela , Leelarathna Lalantha , Acerini Carlo L , Campbell Fiona , Shah Viral N , Criego Amy , Evans Mark L , Dunger David B , Kollman Craig , Bergenstal Richard M , Hovorka Roman
Published: July 2017

Introduction

Despite therapeutic advances, many individuals with type 1 diabetes are unable to achieve tight glycaemic target without increasing the risk of hypoglycaemia. The objective of this study is to determine the effectiveness of a 3-month day-and-night home closed-loop glucose control combined with a pump suspend feature, compared with sensor-augmented insulin pump therapy in youths and adults with suboptimally controlled type 1 diabetes.

Methods and analysis

The study adopts an open-label, multi-centre, multi-national (UK and USA), randomised, single-period, parallel design and aims for 84 randomised patients. Participants are youths (6–21 years) or adults (>21 years) with type 1 diabetes treated with insulin pump therapy and suboptimal glycaemic control (glycated haemoglobin (HbA1c) ≥7.5% (58 mmol/mol) and ≤10% (86 mmol/mol)). Following a 4-week run-in period, eligible participants will be randomised to a 3-month use of automated closed-loop insulin delivery combined with pump suspend feature or to sensor-augmented insulin pump therapy. Analyses will be conducted on an intention-to-treat basis. The primary outcome is the time spent in the target glucose range from 3.9 to 10.0 mmol/L based on continuous glucose monitoring levels during the 3-month free-living phase. Secondary outcomes include HbA1c at 3 months, mean glucose, time spent below and above target; time with glucose levels <3.5 and <2.8 mmol/L; area under the curve when sensor glucose is <3.5 mmol/L, time with glucose levels >16.7 mmol/L, glucose variability; total, basal and bolus insulin dose and change in body weight. Participants’ and their families’ perception in terms of lifestyle change, daily diabetes management and fear of hypoglycaemia will be evaluated.

Ethics and dissemination

Ethics/institutional review board approval has been obtained. Before screening, all participants/guardians will be provided with oral and written information about the trial. The study will be disseminated by peer-reviewed publications and conference presentations.

Trial registration number

NCT02523131; Pre-results.
Advancing Concussion Assessment in Pediatrics (A-CAP): a prospective, concurrent cohort, longitudinal study of mild traumatic brain injury in children: study protocol
Authors: Yeates Keith Owen , Beauchamp Miriam , Craig William , Doan Quynh , Zemek Roger , Bjornson Bruce H , Gravel Jocelyn , Mikrogianakis Angelo , Goodyear Bradley , Abdeen Nishard , Beaulieu Christian , Dehaes Mathieu , Deschenes Sylvain , Harris Ashley , Lebel Catherine , Lamont Ryan , Williamson Tyler , Barlow Karen Maria , Bernier Francois , Brooks Brian L , Emery Carolyn , Freedman Stephen B , Kowalski Kristina , Mrklas Kelly , Tomfohr-Madsen Lianne , Schneider Kathryn J
Published: July 2017

Introduction

Paediatric mild traumatic brain injury (mTBI) is a public health burden. Clinicians urgently need evidence-based guidance to manage mTBI, but gold standards for diagnosing and predicting the outcomes of mTBI are lacking. The objective of the Advancing Concussion Assessment in Pediatrics (A-CAP) study is to assess a broad pool of neurobiological and psychosocial markers to examine associations with postinjury outcomes in a large sample of children with either mTBI or orthopaedic injury (OI), with the goal of improving the diagnosis and prognostication of outcomes of paediatric mTBI.

Methods and analysis

A-CAP is a prospective, longitudinal cohort study of children aged 8.00–16.99 years with either mTBI or OI, recruited during acute emergency department (ED) visits at five sites from the Pediatric Emergency Research Canada network. Injury information is collected in the ED; follow-up assessments at 10 days and 3 and 6 months postinjury measure a variety of neurobiological and psychosocial markers, covariates/confounders and outcomes. Weekly postconcussive symptom ratings are obtained electronically. Recruitment began in September 2016 and will occur for approximately 24 months. Analyses will test the major hypotheses that neurobiological and psychosocial markers can: (1) differentiate mTBI from OI and (2) predict outcomes of mTBI. Models initially will focus within domains (eg, genes, imaging biomarkers, psychosocial markers), followed by multivariable modelling across domains. The planned sample size (700 mTBI, 300 OI) provides adequate statistical power and allows for internal cross-validation of some analyses.

Ethics and dissemination

The ethics boards at all participating institutions have approved the study and all participants and their parents will provide informed consent or assent. Dissemination will follow an integrated knowledge translation plan, with study findings presented at scientific conferences and in multiple manuscripts in peer-reviewed journals.
PIRATE project: point-of-care, informatics-based randomised controlled trial for decreasing overuse of antibiotic therapy in Gram-negative bacteraemia
Authors: Huttner Angela , Albrich Werner C , Bochud Pierre-Yves , Gayet-Ageron Angèle , Rossel Anne , Dach Elodie von , Harbarth Stephan , Kaiser Laurent
Published: July 2017

Introduction

Antibiotic overuse drives antibiotic resistance. The optimal duration of antibiotic therapy for Gram-negative bacteraemia (GNB), a common community and hospital-associated infection, remains unknown and unstudied via randomised controlled trials (RCTs).

Methods and analysis

This investigator-initiated, multicentre, non-inferiority, informatics-based point-of-care RCT will randomly assign adult hospitalised patients receiving microbiologically efficacious antibiotic(s) for GNB to (1) 14 days of antibiotic therapy, (2) 7 days of therapy or (3) an individualised duration determined by clinical response and 75% reduction in peak C reactive protein (CRP) values. The randomisation will occur in equal proportions (1:1:1) on day 5 (±1) of efficacious antibiotic therapy as determined by antibiogram; patients, their physicians and study investigators will be blind to treatment duration allocation until the day of antibiotic discontinuation. Immunosuppressed patients and those with GNB due to complicated infections (endocarditis, osteomyelitis, etc) and/or non-fermenting bacilli (Acinetobacterspp,Burkholderiaspp,Pseudomonasspp)Brucellaspp,Fusobacteriumspp or polymicrobial growth with Gram-positive organisms will be ineligible. The primary outcome is incidence of clinical failure at day 30; secondary outcomes include clinical failure, all-cause mortality and incidence ofClostridiumdifficileinfection in the 90-day study period. An interim safety analysis will be performed after the first 150 patients have been followed for ≤30 days. Given a chosen margin of 10%, the required sample size to determine non-inferiority is roughly 500 patients. Analyses will be performed on both intention-to-treat and per-protocol populations.

Ethics and dissemination

Ethics approval was obtained from the cantonal ethics committees of all three participating sites. Results of the main trial and each of the secondary endpoints will be submitted for publication in a peer-reviewed journal.

Trial registration number

This trial is registered atwww.clinicaltrials.gov(NCT03101072; pre-results).
Onyx embolization prior to stereotactic radiosurgery for brain arteriovenous malformations: a single-center treatment algorithm
Authors: Nerva John D , Barber Jason , Levitt Michael R , Rockhill Jason K , Hallam Danial K , Ghodke Basavaraj V , Sekhar Laligam N , Kim Louis J
Published: July 2017

Background

Embolization before stereotactic radiosurgery (SRS) for brain arteriovenous malformations (BAVMs) is controversial.

Objective

To compare clinical and radiographic outcomes in patients undergoing pre-SRS embolization with ethylene copolymer (Onyx) with outcomes in patients undergoing SRS alone.

Methods

Seventy consecutive patients with BAVMs who underwent SRS were retrospectively reviewed. Univariate and multivariate analyses were performed to assess the factors associated with radiographic obliteration and complication.

Results

Forty-one (59%) patients presented without BAVM rupture and 29 (41%) patients presented with rupture. Pre-SRS embolization was used in 20 patients (28.6%; 7 unruptured and 13 ruptured). Twenty-five of 70 (36%) patients sustained a complication from treatment, including 6 (9%) patients with a post-SRS latency period hemorrhage. Ten (14%) patients had persistent neurological deficits after treatment. Functional outcome (as modified Rankin Scale), complication rate, and radiographic obliteration at last follow-up were not significantly different between embolized and non-embolized groups in both unruptured and ruptured BAVMs. For unruptured BAVMs, 3- and 5-year rates of radiographic obliteration were 23% and 73% for non-embolized patients and 20% and 60% for embolized patients, respectively. For ruptured BAVMs, 3- and 5-year rates of radiographic obliteration were 45% and 72% for non-embolized patients and 53% and 82% for embolized patients, respectively.

Conclusion

Pre-SRS embolization with Onyx was not associated with worse clinical or radiographic outcomes than SRS treatment without embolization. Pre-SRS embolization has a low complication rate and can safely be used to target high-risk BAVM features in carefully selected patients destined for SRS.
Neuroprotective strategies following intraparenchymal hemorrhage
Authors: Babadjouni Robin Moshe , Radwanski Ryan E , Walcott Brian P , Patel Arati , Durazo Ramon , Hodis Drew M , Emanuel Benjamin A , Mack William J
Published: July 2017

Intracerebral hemorrhage and, more specifically, intraparenchymal hemorrhage, are devastating disease processes with poor clinical outcomes. Primary injury to the brain results from initial hematoma expansion while secondary hemorrhagic injury occurs from blood-derived products such as hemoglobin, heme, iron, and coagulation factors that overwhelm the brains natural defenses. Novel neuroprotective treatments have emerged that target primary and secondary mechanisms of injury. Nonetheless, translational application of neuroprotectants from preclinical to clinical studies has yet to show beneficial clinical outcomes. This review summarizes therapeutic agents and neuroprotectants in ongoing clinical trials aimed at targeting primary and secondary mechanisms of injury after intraparenchymal hemorrhage.
Smoke-free signage in public parks: impacts on smoking behaviour
Authors: Platter Heather N , Pokorny Steven B
Published: July 2017

Objective

Behavioural interventions, such as smoke-free signage, are used to support air quality in public outdoor spaces that are not protected by a smoke-free policy, such as states with preemptive clause legislation. However, there is little evidence of the effectiveness of these interventions. This paper is an evaluation of whether smoke-free signage posted in public parks altered smoking behaviours of park patrons.

Methods

A time-series quasi-experimental design was used. Cigarette butts were collected at the same day and time every week in ten amenities within four parks in 2011. Each park completed a baseline period until a stable trend emerged at six weeks, then received smoke-free signage for the six week intervention period. There were 1684 cigarette butts collected during baseline and 1008 collected during the intervention phase.

Findings

Wilcoxon signed-rank test demonstrated that smoking at seven out of ten amenities decreased and the overall decrease was significant at p=0.028. Individual parks and amenities grouped by type did not experience a statistically significant change. A neighbourhood median income trend was visually discovered, revealing that as income increased, there was a greater decrease in cigarette butts.

Conclusions

This study provides evidence on the impact of smoke-free signage not supported by local ordinance in public parks using a reproducible measure. States, especially those with a preemptive clause legislation, may benefit from incorporating smoke-free signage in public areas to protect community members from exposure to tobacco smoke, reduce littering, and denormalise smoking.
Gq-activated fibroblasts induce cardiomyocyte action potential prolongation and automaticity in a three-dimensional microtissue environment
Authors: Kofron C. M. , Kim T. Y. , King M. E. , Xie A. , Feng F. , Park E. , Qu Z. , Choi B.-R. , Mende U.
Published: July 2017

Cardiac fibroblasts (CFs) are known to regulate cardiomyocyte (CM) function in vivo and in two-dimensional in vitro cultures. This study examined the effect of CF activation on the regulation of CM electrical activity in a three-dimensional (3-D) microtissue environment. Using a scaffold-free 3-D platform with interspersed neonatal rat ventricular CMs and CFs, Gq-mediated signaling was selectively enhanced in CFs by Gαqadenoviral infection before coseeding with CMs in nonadhesive hydrogels. After 3 days, the microtissues were analyzed by signaling assay, histological staining, quantitative PCR, Western blots, optical mapping with voltage- or Ca2+-sensitive dyes, and microelectrode recordings of CF resting membrane potential (RMPCF). Enhanced Gqsignaling in CFs increased microtissue size and profibrotic and prohypertrophic markers. Expression of constitutively active Gαqin CFs prolonged CM action potential duration (by 33%) and rise time (by 31%), prolonged Ca2+transient duration (by 98%) and rise time (by 65%), and caused abnormal electrical activity based on depolarization-induced automaticity. Constitutive Gqactivation in CFs also depolarized RMPCFfrom –33 to −20 mV and increased connexin 43 and connexin 45 expression. Computational modeling confers that elevated RMPCFand increased cell-cell coupling between CMs and CFs in a 3-D environment could lead to automaticity. In conclusion, our data demonstrate that CF activation alone is capable of altering action potential and Ca2+transient characteristics of CMs, leading to proarrhythmic electrical activity. Our results also emphasize the importance of a 3-D environment where cell-cell interactions are prevalent, underscoring that CF activation in 3-D tissue plays a significant role in modulating CM electrophysiology and arrhythmias.

NEW & NOTEWORTHY In a three-dimensional microtissue model, which lowers baseline activation of cardiac fibroblasts but enables cell-cell, paracrine, and cell-extracellular matrix interactions, we demonstrate that selective cardiac fibroblast activation by enhanced Gqsignaling, a pathophysiological trigger in the diseased heart, modulates cardiomyocyte electrical activity, leading to proarrhythmogenic automaticity.
Vitamin C mitigates oxidative/nitrosative stress and inflammation in doxorubicin-induced cardiomyopathy
Authors: Akolkar Gauri , da Silva Dias Danielle , Ayyappan Prathapan , Bagchi Ashim K. , Jassal Davinder S. , Salemi Vera Maria Cury , Irigoyen Maria Claudia , De Angelis Katia , Singal Pawan K.
Published: July 2017

Increase in oxidative/nitrosative stress is one of the mechanisms associated with the development of cardiotoxicity due to doxorubicin (Dox), a potent chemotherapy drug. Previously, we reported mitigation of Dox-induced oxidative/nitrosative stress and apoptosis by vitamin C (Vit C) in isolated cardiomyocytes. In the present in vivo study in rats, we investigated the effect of prophylactic treatment with Vit C on Dox-induced apoptosis, inflammation, oxidative/nitrosative stress, cardiac dysfunction, and Vit C transporter proteins. Dox (cumulative dose: 15 mg/kg) in rats reduced systolic and diastolic cardiac function and caused structural damage. These changes were associated with a myocardial increase in reactive oxygen species, reduction in antioxidant enzyme activities, increased expression of apoptotic proteins, and inflammation. Dox also caused an increase in the expression of proapoptotic proteins Bax, Bnip-3, Bak, and caspase-3. An increase in oxidative/nitrosative stress attributable to Dox was indicated by an increase in superoxide, protein carbonyl formation, lipid peroxidation, nitric oxide (NO), NO synthase (NOS) activity, protein nitrosylation, and inducible NOS protein expression. Dox increased the levels of cardiac proinflammatory cytokines TNF-α, IL-1β, and IL-6, whereas the expression of Vit C transporter proteins (sodium-ascorbate cotransporter 2 and glucose transporter 4) was reduced. Prophylactic and concurrent treatment with Vit C prevented all these changes and improved survival in the Vit C + Dox group. Vit C also improved Dox-mediated systolic and diastolic dysfunctions and structural damage. These results suggest a cardioprotective role of Vit C in Dox-induced cardiomyopathy by reducing oxidative/nitrosative stress, inflammation, and apoptosis, as well as improving Vit C transporter proteins.

NEW & NOTEWORTHY This in vivo study provides novel data that vitamin C improves cardiac structure and function in doxorubicin-induced cardiomyopathy by reducing oxidative/nitrosative stress, apoptosis, and inflammation along with upregulation of cardiac vitamin C transporter proteins. The latter may have a crucial role in improving antioxidant status in this cardiomyopathy.
Circulating acylcarnitine profile in human heart failure: a surrogate of fatty acid metabolic dysregulation in mitochondria and beyond
Authors: Ruiz Matthieu , Labarthe François , Fortier Annik , Bouchard Bertrand , Thompson Legault Julie , Bolduc Virginie , Rigal Odile , Chen Jane , Ducharme Anique , Crawford Peter A. , Tardif Jean-Claude , Des Rosiers Christine
Published: July 2017

Heart failure (HF) is associated with metabolic perturbations, particularly of fatty acids (FAs), which remain to be better understood in humans. This study aimed at testing the hypothesis that HF patients with reduced ejection fraction display systemic perturbations in levels of energy-related metabolites, especially those reflecting dysregulation of FA metabolism, namely, acylcarnitines (ACs). Circulating metabolites were assessed using mass spectrometry (MS)-based methods in two cohorts. The main cohort consisted of 72 control subjects and 68 HF patients exhibiting depressed left ventricular ejection fraction (25.9 ± 6.9%) and mostly of ischemic etiology with ≥2 comorbidities. HF patients displayed marginal changes in plasma levels of tricarboxylic acid cycle-related metabolites or indexes of mitochondrial or cytosolic redox status. They had, however, 22–79% higher circulating ACs, irrespective of chain length ( P < 0.0001, adjusted for sex, age, renal function, and insulin resistance, determined by shotgun MS/MS), which reflects defective mitochondrial β-oxidation, and were significantly associated with levels of NH2-terminal pro-B-type natriuretic peptide levels, a disease severity marker. Subsequent extended liquid chromatography-tandem MS analysis of 53 plasma ACs in a subset group from the primary cohort confirmed and further substantiated with a comprehensive lipidomic analysis in a validation cohort revealed in HF patients a more complex circulating AC profile. The latter included dicarboxylic-ACs and dihydroxy-ACs as well as very long chain (VLC) ACs or sphingolipids with VLCFAs (>20 carbons), which are proxies of dysregulated FA metabolism in peroxisomes. Our study identified alterations in circulating ACs in HF patients that are independent of biological traits and associated with disease severity markers. These alterations reflect dysfunctional FA metabolism in mitochondria but also beyond, namely, in peroxisomes, suggesting a novel mechanism contributing to global lipid perturbations in human HF.

NEW & NOTEWORTHY Mass spectrometry-based profiling of circulating energy metabolites, including acylcarnitines, in two cohorts of heart failure versus control subjects revealed multiple alterations in fatty acid metabolism in peroxisomes in addition to mitochondria, thereby highlighting a novel mechanism contributing to global lipid perturbations in heart failure.

Listen to this article’s corresponding podcast at http://ajpheart.podbean.com/e/acylcarnitines-in-human-heart-failure/ .
Tobacco Product Use Patterns, and Nicotine and Tobacco-Specific Nitrosamine Exposure: NHANES 1999–2012
Authors: Choi Kelvin , Sabado Melanie , El-Toukhy Sherine , Vogtmann Emily , Freedman Neal D. , Hatsukami Dorothy
Published: July 2017

Background: Few studies have examined differences in product consumption patterns and nicotine and tobacco-specific nitrosamines (TSNA) exposure between single versus dual- and poly-tobacco users. We applied the Tobacco Product Use Patterns (T-PUPs) model to fill this gap in the literature.

Methods: Data from adults (age ≥18 years) who used any tobacco products during the 5 days prior to participating in the 1999–2012 National Health and Nutrition Examination Survey (NHANES) were analyzed. Participants were classified into seven T-PUPs: (1) cigarettes only, (2) noncigarette combustibles only, (3) noncombustibles only, (4) dual noncigarette combustibles and noncombustibles, (5) dual cigarettes and noncombustibles, (6) dual cigarettes and noncigarette combustibles, and (7) poly-tobacco use. Weighted regression models were used to compare product consumption, serum cotinine, and urinary total 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (i.e., NNAL) levels between single-, dual-, and poly-tobacco T-PUPs.

Results: Dual- and poly-tobacco T-PUPs were associated with lower product consumption compared with single-product T-PUPs only in some cases (e.g., dual cigarette and noncombustible users smoked cigarettes on 0.6 fewer days in the past 5 days compared with cigarette-only users; P < 0.05). Dual- and poly-tobacco T-PUPs had either nondistinguishable or higher levels of serum cotinine and urinary total NNAL than corresponding single-product T-PUPs.

Conclusions: Product consumption, and nicotine and TSNAs exposure of dual- and poly-tobacco product category users somewhat differ from those of single-product category users as defined by the T-TUPs model.

Impact: Higher levels of cotinine and NNAL among dual- and poly-tobacco T-TUPs users compared with the single-product T-TUPs users may indicate health concerns. Cancer Epidemiol Biomarkers Prev; 26(10); 1525–30. ©2017 AACR.
Opportunities and Challenges for Environmental Exposure Assessment in Population-Based Studies
Authors: Patel Chirag J. , Kerr Jacqueline , Thomas Duncan C. , Mukherjee Bhramar , Ritz Beate , Chatterjee Nilanjan , Jankowska Marta , Madan Juliette , Karagas Margaret R. , McAllister Kimberly A. , Mechanic Leah E. , Fallin M. Daniele , Ladd-Acosta Christine , Blair Ian A. , Teitelbaum Susan L. , Amos Christopher I.
Published: July 2017

A growing number and increasing diversity of factors are available for epidemiological studies. These measures provide new avenues for discovery and prevention, yet they also raise many challenges for adoption in epidemiological investigations. Here, we evaluate 1) designs to investigate diseases that consider heterogeneous and multidimensional indicators of exposure and behavior, 2) the implementation of numerous methods to capture indicators of exposure, and 3) the analytical methods required for discovery and validation. We find that case-control studies have provided insights into genetic susceptibility but are insufficient for characterizing complex effects of environmental factors on disease development. Prospective and two-phase designs are required but must balance extended data collection with follow-up of study participants. We discuss innovations in assessments including the microbiome; mass spectrometry and metabolomics; behavioral assessment; dietary, physical activity, and occupational exposure assessment; air pollution monitoring; and global positioning and individual sensors. We claim the the availability of extensive correlated data raises new challenges in disentangling specific exposures that influence cancer risk from among extensive and often correlated exposures. In conclusion, new high-dimensional exposure assessments offer many new opportunities for environmental assessment in cancer development. Cancer Epidemiol Biomarkers Prev; 26(9); 1370–80. ©2017 AACR.
Tuberin Regulates Prostaglandin Receptor–Mediated Viability, via Rheb, in mTORC1-Hyperactive Cells
Authors: Li Chenggang , Liu Xiaolei , Liu Yang , Zhang Erik , Medepalli Kantha , Masuda Kouhei , Li Na , Wikenheiser-Brokamp Kathryn A. , Osterburg Andrew , Borchers Michael T. , Kopras Elizabeth J. , Plas David R. , Sun Julia , Franz David N. , Capal Jamie K. , Mays Maxwell , Sun Yang , Kwiatkowski David J. , Alayev Anya , Holz Marina K. , Krueger Darcy A. , Siroky Brian J. , Yu Jane J.
Published: July 2017

Tuberous sclerosis complex (TSC) is a tumor-suppressor syndrome affecting multiple organs, including the brain, skin, kidneys, heart, and lungs. TSC is associated with mutations in TSC1 or TSC2, resulting in hyperactivation of mTOR complex 1 (mTORC1). Clinical trials demonstrate that mTORC1 inhibitors decrease tumor volume and stabilize lung function in TSC patients; however, mTOR inhibitors are cytostatic not cytocidal, and long-term benefits and toxicities are uncertain. Previously, we identified rapamycin-insensitive upregulation of cyclooxygenase 2 (PTGS2/COX2) and prostaglandin E2 (PGE2) production in TSC2-deficient cells and postulated that the action of excess PGE2 and its cognate receptors (EP) contributes to cell survival. In this study, we identify upregulation of EP3 (PTGER3) expression in TSC2-deficient cells, TSC renal angiomyolipomas, lymphangioleiomyomatosis lung nodules, and epileptic brain tubers. TSC2 negatively regulated EP3 expression via Rheb in a rapamycin-insensitive manner. The EP3 antagonist, L-798106, selectively suppressed the viability of TSC2-deficient cells in vitro and decreased the lung colonization of TSC2-deficient cells. Collectively, these data reveal a novel function of TSC2 and Rheb in the regulation of EP3 expression and cell viability.

Implications: Therapeutic targeting of an aberrant PGE2-EP3 signaling axis may have therapeutic benefit for TSC patients and for other mTOR-hyperactive neoplasms. Mol Cancer Res; 15(10); 1318–30. ©2017 AACR.
Priorities for Cardiovascular Outcomes Research
Authors: Khazanie Prateeti , Krumholz Harlan M. , Kiefe Catarina I. , Kressin Nancy R. , Wells Barbara , Wang Tracy Y. , Peterson Eric D.
Published: July 2017

The Centers for Cardiovascular Outcomes Research (CCORs) held a meeting to review how cardiovascular outcomes research had evolved in the decade since the National Heart, Lung, and Blood Institute 2004 working group report and to consider future directions. The conference involved representatives from governmental agencies, outcomes research thought leaders, and public and private healthcare partners. The main purposes of this meeting were to (1) advance collaborative high-yield, high-impact outcomes research; (2) identify priorities and barriers to important cardiovascular outcomes research; and (3) define future needs for the field. This report highlights the key topics covered during the meeting, including an examination of the recent history of outcomes research, an evaluation of the current academic climate, and a vision for the future of cardiovascular outcomes research.
Association of Surgeon Age and Experience With Congenital Heart Surgery Outcomes
Authors: Anderson Brett R. , Wallace Amelia S. , Hill Kevin D. , Gulack Brian C. , Matsouaka Roland , Jacobs Jeffrey P. , Bacha Emile A. , Glied Sherry A. , Jacobs Marshall L.
Published: July 2017

Background—

Surgeon experience concerns both families of children with congenital heart disease and medical providers. Relationships between surgeon seniority and patient outcomes are often assumed, yet there are little data.

Methods and Results—

This national study used linked data from the American Medical Association Physician Masterfile and the Society of Thoracic Surgeons-Congenital Heart Surgery Database to examine associations between surgeon years since medical school and major morbidity/mortality for children undergoing cardiac surgery. Sensitivity analyses explored the effects of patient characteristics, institutional/surgeon volumes, and various measures of institutional surgeon team experience. In secondary analyses, major morbidity and mortality were examined as separate end points. We identified 206 congenital heart surgeons from 91 centers performing 62 851 index operations (2010–2014). Median time from school was 25 years (range 9–55 years). A major morbidity/mortality occurred in 11.5% of cases. In multivariable analyses, the odds of major morbidity/mortality were similar for early-career (<15 years from medical school, ≈<40 years old), midcareer (15–24 years, ≈40–50 years old), and senior surgeons (25–35 years, ≈50–60 years old). The odds of major morbidity/mortality were ≈25% higher for operations performed by very senior surgeons (35–55 years from school, ≈60–80 years old; n=9044 cases). Results were driven by differences in morbidity. In extensive sensitivity analyses, these effects remained constant.

Conclusions—

In this study of >200 congenital heart surgeons, we found patient outcomes for surgeons with the fewest years of experience to be comparable to those of their midcareer and senior colleagues, within the context of existing referral and support practices. Very senior surgeons had higher risk-adjusted odds of major morbidity/mortality. Contemporary approaches to training, referral, mentoring, surgical planning, and other support practices might contribute to the observed outcomes of junior congenital heart surgeons being comparable to those of more experienced colleagues. Understanding and disseminating these practices might benefit the medical community at large.
Severe Aortic Stenosis in Dialysis Patients
Authors: Kawase Yuichi , Taniguchi Tomohiko , Morimoto Takeshi , Kadota Kazushige , Iwasaki Keiichiro , Kuwayama Akimune , Ohya Masanobu , Shimada Takenobu , Amano Hidewo , Maruo Takeshi , Fuku Yasushi , Izumi Chisato , Kitai Takeshi , Saito Naritatsu , Minamino‐Muta Eri , Kato Takao , Inada Tsukasa , Inoko Moriaki , Ishii Katsuhisa , Komiya Tatsuhiko , Hanyu Michiya , Minatoya Kenji , Kimura Takeshi ,   on behalf of the CURRENT AS Registry Investigators
Published: July 2017

Background

Characteristics and prognosis of hemodialysis patients with severe aortic stenosis have not yet been well defined.

Methods and Results

The
CURRENT AS
(contemporary outcomes after surgery and medical treatment in patients with severe aortic stenosis) registry, a Japanese multicenter registry, enrolled 3815 consecutive patients with severe aortic stenosis. There were 405 hemodialysis patients (initial aortic valve replacement [
AVR
] group: N=135 [33.3%], and conservative group: N=270) and 3410 nonhemodialysis patients (initial
AVR
group: N=1062 [31.1%], and conservative group: N=2348). The median follow‐up duration after the index echocardiography was 1361 days, with 90% follow‐up rate at 2 years. The cumulative 5‐year incidence of all‐cause death was significantly higher in hemodialysis patients than in nonhemodialysis patients in both the entire cohort (71% versus 40%,
P
<0.001) and in the initial
AVR
group (63.2% versus 17.9%,
P
<0.001). Among hemodialysis patients, the initial
AVR
group as compared with the conservative group was associated with significantly lower cumulative 5‐year incidences of all‐cause death (60.6% versus 75.5%,
P
<0.001) and sudden death (10.2% versus 31.7%,
P
<0.001). Nevertheless, the rate of aortic valve procedure–related death, which predominantly occurred within 6 months of the
AVR
procedure, was markedly higher in the hemodialysis patients than in the nonhemodialysis patients (21.2% and 2.3%,
P
<0.001).

Conclusions

Among hemodialysis patients with severe aortic stenosis, the initial
AVR
strategy as compared with the conservative strategy was associated with significantly lower long‐term mortality risk, particularly the risk for sudden death, although the effect size for the survival benefit of the initial
AVR
strategy was smaller than that in the nonhemodialysis patients.
Memory as Resistance, and the Telling of a Dream
Authors: Gray Paul
Published: July 2017

Traditional analytic orientation to memory as subject to repression has overshadowed examination of some of the ego's other activities bearing on memory. The author examines the defensive use of memory with the analytic goal of maximum autonomous access for the patient to the ego's previously unconscious management of intrapsychic conflict. A close scrutiny of an example of this in the form of the telling of a dream explores this resistance process and illustrates a technical approach. Some aspects of this perspective are considered in relation to traditional approaches to dream material. Certain technical priorities for differing clinical settings are discussed.
An Investigation into Some Implications of a Vygotskian Perspective on the Origins of Mind: Psychoanalysis and Vygotskian Psychology, Part I
Authors: Wilson Arnold , Weinstein Lissa
Published: July 2017

The Russian psychologist Lev Vygotsky proposed an analysis of language, thought, and internalization that has direct relevance to the current concerns of psychoanalysts. Striking methodological and conceptual similarities and useful complementarities with psychoanalysis are discovered when one peers beneath the surface of Vygotskian psychology. Our adaptation of Vygotsky's views expands upon Freud's assigned role to language in the topographic model. We suggest that the analysand's speech offers several windows into the history of the individual, through prosody, tropes, word meaning, and word sense. We particularly emphasize Vygotsky's views on the genesis and utilization of word meanings. The acquisition of word meanings will contain key elements of the internal climate present when the word meaning was forged. Bearing this in mind, crucial theoretical questions follow, such as how psychoanalysis is to understand the unconscious fantasies, identifications, anxieties, and defenses associated with the psychodynamics of language acquisition and later language usage. We propose that the clinical situation is an ideal place to test these hypotheses.
From Analytic Surface to Analytic Space
Authors: Poland Warren S.
Published: July 2017

Utilizing a clinical illustration, the concept of the surface of the patient's mind, which arose early in analytic history, is reexamined in relation to the analytic space, the unique affective and communicative dyadic context of the analytic process. The shift from analytic surface to analytic space reflects in clinical theory the metapsychological shift from early structural views to current appreciation of compromise formation. Also, this approach permits broadening of consideration of active unconscious forces in both the patient and the analyst.