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Many catabolic stimuli, including interleukin-1 (IL-1) in combination with oncostatin M (OSM), promote cartilage breakdown via the induction of collagen-degrading collagenases such as matrix metalloproteinase 1 (MMP1) and MMP13 in human articular chondrocytes. Indeed, joint diseases with an inflammatory component are characterised by excessive extracellular matrix (ECM) catabolism. Importantly, protein kinase C (PKC) signalling has a primary role in cytokine-induced MMP1/13 expression, and is known to regulate cellular functions associated with pathologies involving ECM remodelling. At present, substrates downstream of PKC remain undefined. Herein, we show that both IL-1- and OSM-induced phosphorylation of protein kinase D (PKD) in human chondrocytes is strongly associated with signalling via the atypical PKCι isoform. Consequently, inhibiting PKD activation with a pan-PKD inhibitor significantly reduced the expression of MMP1/13. Specific gene silencing of the PKD isoforms revealed that only PKD3 (PRKD3) depletion mirrored the observed MMP repression, indicative of the pharmacological inhibitor specifically affecting only this isoform. PRKD3 silencing was also shown to reduce serine phosphorylation of signal transducer and activator of transcription 3 (STAT3) as well as phosphorylation of all three mitogen-activated protein kinase groups. This altered signalling following PRKD3 silencing led to a significant reduction in the expression of the activator protein-1 (AP-1) genes FOS and JUN, critical for the induction of many MMPs including MMP1/13. Furthermore, the AP-1 factor activating transcription factor 3 (ATF3) was also reduced concomitant with the observed reduction in MMP13 expression. Taken together, we highlight an important role for PKD3 in the pro-inflammatory signalling that promotes cartilage destruction.

Irreversible cartilage collagen breakdown by the collagenolytic matrix metalloproteinases (MMPs)-1 and MMP-13 represents a key event in pathologies associated with tissue destruction such as arthritis. Inflammation is closely associated with such pathology and occurs in both rheumatoid and osteoarthritis making it highly relevant to the prevailing tissue damage that characterises these diseases. The inflammation-induced activating protein-1 (AP-1) transcription factor is an important regulator of both MMP1 and MMP13 genes with interplay between signalling pathways contributing to their expression. Here, we have examined the regulation of MMP1 expression, and using in vivo chromatin immunoprecipitation analyses we have demonstrated that cFos bound to the AP-1 cis element within the proximal MMP1 promoter only when the gene was transcriptionally silent as previously observed for MMP13. Subsequent small interfering RNA-mediated silencing confirmed however, that cFos significantly contributes to MMP1 expression. In contrast, silencing of ATF3 (a prime MMP13 modulator) did not affect MMP1 expression whilst silencing of the Wnt-associated regulator cysteine- serine-rich nuclear protein-1 (CSRNP1) resulted in substantial repression of MMP1 but not MMP13. Furthermore, following an early transient peak in expression of CSRNP1 at the mRNA and protein levels similar to that seen for cFOS, CSRNP1 expression subsequently persisted unlike cFOS. Finally, DNA binding assays indicated that the binding of CSRNP1 to the AP-1 consensus-like sequences within the proximal promoter regions of MMP1 and MMP13 was preferentially selective for MMP1 whilst activating transcription factor 3 (ATF3) binding was exclusive to MMP13. These data further extend our understanding of the previously reported differential regulation of these MMP genes, and strongly indicate that although cFos modulates the expression of MMP1/13, downstream factors such as CSRNP1 and ATF3 ultimately serve as transcriptional regulators in the context of an inflammatory stimulus for these potent collagenolytic MMPs.

Escherichia coli serotype O117 (ECO117) are pathogenic bacteria that produce Shiga toxin. Repeating units of the O antigen of ECO117 have the pentasaccharide structure [4-D-GalNAcβ1-3-L-Rhaα1-4-D-Glcα1-4-D-Galβ1-3-D-GalNAcα1-]n. The related non-pathogenic serotype (ECO107) contains a GlcNAc residue instead of Glc in the repeating unit, and the biosynthetic enzymes involved are almost identical. We assembled these repeating units based on GalNAcα-diphosphate-phenylundecyl (GalNAcα-PP-PhU), an analog of the natural intermediate GalNAc-diphosphate-undecaprenyl. We previously characterized α1,4-Glc-transferase WclY from ECO117 that transfers the Glc residue to Galβ1-3GalNAcα-PP-PhU and showed that Arg194Cys mutants of WclY are active α1,4-GlcNAc-transferases. In this work, the reaction products of WclY were used as acceptor substrates for the final enzymes in pathway, L-Rha-transferase WclX, and GalNAc-transferase WclW, demonstrating a complete synthesis of the ECO117 and O107 repeating units. WclX transfers L-Rha with high specificity for the WclY enzyme product as the acceptor and for TDP-L-Rha as the donor substrate. A number of highly conserved sequence motifs were identified (DDGSxD, DxDD, and YR). Mutational analysis revealed several Asp residues are essential for the catalysis of L-Rha transfer, while mutations of Asp44 and R212 substantially reduced the activity of WclX. WclW is a GT2 enzyme specific for UDP-GalNAc but with broad specificity for the acceptor substrate. Using L-Rhaα-p-nitrophenyl as an acceptor for WclW, the reaction product was analyzed by NMR demonstrating that GalNAc was transferred in a β1-3 linkage to L-Rha. The in vitro synthesis of the repeating units allows the production of vaccine candidates and identifies potential targets for inhibition of O antigen biosynthesis., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Electrocardiographic imaging (ECGI) generates electrophysiological (EP) biomarkers while cardiovascular magnetic resonance (CMR) imaging provides data about myocardial structure, function and tissue substrate. Combining this information in one examination is desirable but requires an affordable, reusable, and high-throughput solution. We therefore developed the CMR-ECGI vest and carried out this technical development study to assess its feasibility and repeatability in vivo., Methods: CMR was prospectively performed at 3T on participants after collecting surface potentials using the locally designed and fabricated 256-lead ECGI vest. Epicardial maps were reconstructed to generate local EP parameters such as activation time (AT), repolarization time (RT) and activation recovery intervals (ARI). 20 intra- and inter-observer and 8 scan re-scan repeatability tests., Results: 77 participants were recruited: 27 young healthy volunteers (HV, 38.9 ± 8.5 years, 35% male) and 50 older persons (77.0 ± 0.1 years, 52% male). CMR-ECGI was achieved in all participants using the same reusable, washable vest without complications. Intra- and inter-observer variability was low (correlation coefficients [r s ] across unipolar electrograms = 0.99 and 0.98 respectively) and scan re-scan repeatability was high (r s between 0.81 and 0.93). Compared to young HV, older persons had significantly longer RT (296.8 vs 289.3 ms, p = 0.002), ARI (249.8 vs 235.1 ms, p = 0.002) and local gradients of AT, RT and ARI (0.40 vs 0.34 ms/mm, p = 0,01; 0.92 vs 0.77 ms/mm, p = 0.03; and 1.12 vs 0.92 ms/mm, p = 0.01 respectively)., Conclusion: Our high-throughput CMR-ECGI solution is feasible and shows good reproducibility in younger and older participants. This new technology is now scalable for high throughput research to provide novel insights into arrhythmogenesis and potentially pave the way for more personalised risk stratification., Clinical Trial Registration: Title: Multimorbidity Life-Course Approach to Myocardial Health-A Cardiac Sub-Study of the MRC National Survey of Health and Development (NSHD) (MyoFit46). National Clinical Trials (NCT) number: NCT05455125. URL: https://clinicaltrials.gov/ct2/show/NCT05455125?term=MyoFit&draw=2&rank=1., (© 2023. The Author(s).)

Objective: The onset of the COVID-19 pandemic in March of 2020 forced a rapid pivot to telehealth and compelled a use-case experiment in specialty telehealth neurology movement disorders care. The aims of this study were to quantify the potential benefit of telehealth as an option to the Parkinson's disease community as shown by the first 9 months of the COVID-19 pandemic, and to quantify the potential impact of the absence of a deep brain stimulation (DBS) telehealth option on DBS patient follow-up., Methods: New patient visits to the Inova Parkinson's and Movement Disorder's Center from April to December 2020 (9 months) were retrospectively reviewed for telehealth vs. in-person, demographics (age, gender, race, primary insurance), chief complaint, prior movement disorders specialist (MDS) consultation, imaging tests ordered, and distance/travel time from primary zip code to clinic. Additionally, DBS programming visit volume from April to December 2020 was compared to DBS programming visit volume from April to December 2019., Results: Of the 1,097 new patients seen, 85% were via telehealth ( N = 932) and 15% in person ( N = 165). In the telehealth cohort, 97.75% had not consulted with an MDS before ( N = 911), vs. 87.9% of in-person ( N = 145). Age range was 61.8 +/- 17.9 years (telehealth), 68.8 +/- 16.0 years (in-person). Racial breakdown for telehealth was 60.7% White ( N = 566), 10.4% Black ( N = 97), 7.4% Asian ( N = 69) and 4.5% Hispanic ( N = 42); in-person was 70.9% White ( N = 117), 5.5% Black ( N = 9), 7.9% Asian ( N = 13) and 5.5% Hispanic ( N = 9). Top 5 consultation reasons, top 10 primary insurance providers and imaging studies ordered between the two cohorts were similar. Distance/travel time between primary zip code and clinic were 33.8 +/- 104.8 miles and 42.2 +/- 93.4 min (telehealth) vs. 38.1 +/- 114.7 miles and 44.1 +/- 97.6 min (in-person). DBS programming visits dropped 24.8% compared to the same period the year before (254 visits to 191 visits)., Conclusion: Telehealth-based new patient visits to a Movement Disorders Center appeared successful at increasing access to specialty care. The minimal difference in supporting data highlights the potential parity to in-person visits. With no telehealth option for DBS visits, a significant drop-off was seen in routine DBS management., Competing Interests: SR has received consultancy or speaker fees from Abbott Laboratories. DF has received consultancy or speaker fees from Abbott Laboratories, Abbvie, Amneal, Acorda, GE, Kyowa Kirin, Neurocrine, Sunovion, and also receives compensation as an FTC and Justice Department subject matter expert. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Falconer, Gow, Whitney, Walters and Rogers.)

Background: The life course accumulation of overt and subclinical myocardial dysfunction contributes to older age mortality, frailty, disability and loss of independence. The Medical Research Council National Survey of Health and Development (NSHD) is the world's longest running continued surveillance birth cohort providing a unique opportunity to understand life course determinants of myocardial dysfunction as part of MyoFit46-the cardiac sub-study of the NSHD., Methods: We aim to recruit 550 NSHD participants of approximately 75 years+ to undertake high-density surface electrocardiographic imaging (ECGI) and stress perfusion cardiovascular magnetic resonance (CMR). Through comprehensive myocardial tissue characterization and 4-dimensional flow we hope to better understand the burden of clinical and subclinical cardiovascular disease. Supercomputers will be used to combine the multi-scale ECGI and CMR datasets per participant. Rarely available, prospectively collected whole-of-life data on exposures, traditional risk factors and multimorbidity will be studied to identify risk trajectories, critical change periods, mediators and cumulative impacts on the myocardium., Discussion: By combining well curated, prospectively acquired longitudinal data of the NSHD with novel CMR-ECGI data and sharing these results and associated pipelines with the CMR community, MyoFit46 seeks to transform our understanding of how early, mid and later-life risk factor trajectories interact to determine the state of cardiovascular health in older age., Trial Registration: Prospectively registered on ClinicalTrials.gov with trial ID: 19/LO/1774 Multimorbidity Life-Course Approach to Myocardial Health- A Cardiac Sub-Study of the MCRC National Survey of Health and Development (NSHD)., (© 2022. The Author(s).)

Introduction: Outcomes after deep brain stimulation (DBS) therapy are dependent on good surgical placement in the target nucleus and optimized stimulation parameters through multiple programming sessions. This often requires frequent travel to a specialized DBS center, which presents a challenge for those with limited access. Recently, the FDA approved a remote tele-programming solution for DBS. To determine if remote tele-programming of DBS systems is beneficial and useful for Parkinson's Disease (PD) patients, Parkinson's Foundation hosted a survey in collaboration with Abbott Labs., Methods: The survey was conducted to assess the need for telemedicine among PD patients with DBS and the usability of the telehealth interface for DBS teleprogramming. The survey included two validated instruments: The Effective Accessibility and Accommodation survey (EAA) and the Telehealth Usability Questionnaire (TUQ)., Results: 47 patients completed the EAA and 41 completed the TUQ. Results from the EAA revealed more than a third of PD patients cannot easily get to a clinic for various reasons, and more than a quarter reported difficulty contacting their clinic for advice. Results from the TUQ revealed overall satisfaction with the DBS remote programming telehealth interface and care provided. The majority of respondents reported that remote tele-programming visits are similar in quality to in-person visits., Conclusion: This study provides support for the use of telehealth and tele-programming for DBS management in PD patients. The ability to use remote technologies for care will increase access to DBS and mitigate the disparities that currently prevent access to care., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: In the past decade, catheter ablation (CA) has become a rapidly expanding treatment option for ventricular tachycardia (VT); however it is not commonly utilised for patients with post-myocarditis VT. We aimed to systematically review up-to-date evidence regarding feasibility, effectiveness, and safety of CA, with a specific focus on long-term relapse rate and procedural complications., Methods: A structured electronic database search (PubMed, Embase, Cochrane) of the scientific literature was performed according to PRISMA guidelines for studies describing outcomes at up to 7.3 years after CA. The primary outcome measured was VT recurrence post-ablation. Procedural success was defined as freedom of ventricular arrhythmias (at the end of follow-up after an ablation procedure). The secondary outcome was significant procedural complications which included procedural death, stroke, cardiac tamponade, acute myocardial infarction, major vascular complications, and major bleeding, assessed on a study-by-study basis., Results: A total of 186 patients were included in analysis with most patients (88%) being male. Over the follow-up period, there was a 18% relapse rate ( n  = 34) (confidence interval (CI); 0.12-0.24, I 2 ≈0, p  = 0.77) with the majority of patients remaining VT free for the duration of follow-up. The overall procedural complication rate was 3.0% ( n  = 7) (CI; 0.01-0.07, I 2 ≈0, p  = 0.44), and of note, there were no peri-procedural deaths or heart transplant surgeries reported. However, a single study reported a mortality of 10% ( n  = 2) during the follow-up period., Conclusions: CA is an effective and durable long-term therapeutic strategy for post-myocarditis VT patients with limited relapse rate and very low complication rates based on these non-randomised data. Larger randomised-controlled trials with standardised treatment and long follow-up are required to compare CA versus conventional treatment in the post-acute myocardial phase., Supplementary Information: The online version contains supplementary material available at 10.1007/s42399-022-01137-w., Competing Interests: Conflict of InterestThe authors declare no competing interests., (© The Author(s), under exclusive licence to Springer Nature Switzerland AG 2022.)

Background: The long-term effect of tricuspid regurgitation (TR) after device implantation on long-term mortality remains unknown. In the present study, we sought to examine whether patients undergoing an implantable cardiac device procedure (pacemaker, cardiac defibrillator or cardiac resynchronisation therapy) have an increased risk of TR and to determine the effect of this on long-term survival., Methods: A total of 304 patients who underwent device implant and had pre- and post-implant transthoracic echocardiogram were included in the analysis. All-cause mortality was the study endpoint over a follow-up period of median 11.6 years., Results: New ≥ moderate tricuspid regurgitation post-device implantation developed in 66/304 (21.7%) patients. New right ventricular dysfunction post-device implantation occurred in 59/304 (19.4%) patients. Independent predictors of new RV dysfunction were ischaemic heart disease (OR 4.23, 95% CI 1.58 - 11.33, p = 0.004), left ventricular impairment (OR 2.74, 95% CI 5.41 - 30.00, p < 0.0001) and new ≥ moderate TR (OR 7.72, 95% CI 3.27 - 18.23, p < 0.001). Independent predictors of mortality were new ≥ moderate TR [HR: 3.14 (95% CI 1.29 - 7.63) p = 0.01] and new RV impairment [HR: 2.82 (95% CI 1.33 - 5.98) p = 0.01., Conclusions: Worsening TR and RV dysfunction post-device implantation is common. New post-implant ≥ moderate TR is associated with increased risk of new RV impairment and poor long term (>10 years) survival., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Atrial Fibrillation (AF) is a growing public health issue, associated with significant morbidity and mortality. In addition to pharmacological therapy, catheter ablation is an effective strategy in restoring and maintaining sinus rhythm. However, ablation is not without risk, and AF recurs in a significant proportion of patients. Non-invasive, easily accessible markers or indices that could stratify patients depending on the likelihood of a successful outcome following ablation would allow us to select the most appropriate patients for the procedure, reducing the AF recurrence rate and exposure to potentially life-threatening risks. There has been much attention paid to Brain Natriuretic Peptide (BNP) and N-Terminal prohormone of Brain Natriuretic Peptide (NT-proBNP) as possible predictive markers of successful ablation. Several studies have demonstrated an association between higher pre-ablation levels of these peptides, and a greater likelihood of AF recurrence. Therefore, there may be a role for measuring brain natriuretic peptides levels when selecting patients for catheter ablation., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Almost a third of patients fulfilling current guidelines criteria have suboptimal responses following cardiac resynchronization therapy (CRT). Circulating biomarkers may help identify these patients. We aimed to assess the predictive role of full blood count (FBC) parameters in prognosis of heart failure (HF) patients undergoing CRT device implantation. We enrolled 612 consecutive CRT patients and FBC was measured within 24 hours prior to implantation. The follow-up period was a median of 1652 days (IQR: 837-2612). The study endpoints were i) composite of all-cause mortality or transplant, and ii) reverse left ventricular (LV) remodeling. On multivariate analysis [hazard ratio (HR), 95% confidence interval (CI)] only red cell count (RCC) (p = 0.004), red cell distribution width (RDW) (p < 0.001), percentage of lymphocytes (p = 0.03) and platelet count (p < 0.001) predicted all-cause mortality. Interestingly, RDW (p = 0.004) and platelet count (p = 0.008) were independent predictors of reverse LV remodeling. This is the first powered single-centre study to demonstrate that RDW and platelet count are independent predictors of long-term all-cause mortality and/or heart transplant in CRT patients. Further studies, on the role of these parameters in enhancing patient selection for CRT implantation should be conducted to confirm our findings.

Background: Atrial fibrillation (AF) is associated with an increased risk of cardioembolic stroke. The risk of cardioembolism is not adequately reduced with the administration of oral anticoagulants, since a number of patients continue to experience thromboembolic events despite receiving treatment. Therefore, identification of a circulating biomarker to identify these high-risk patients would be clinically beneficial., Objective: In the present article, we aim to review the available data regarding use of biomarkers to predict cardioembolic stroke in patients with AF., Methods: We performed a thorough search of the literature in order to analyze the biomarkers identified thus far and critically evaluate their clinical significance., Results: A number of biomarkers have been proposed to predict cardioembolic stroke in patients with AF. Some of them are already used in the clinical practice, such as d-dimers, troponins and brain natriuretic peptide. Novel biomarkers, such as the inflammatory growth differentiation factor-15, appear to be promising, while the role of micro-RNAs and genetics appear to be useful as well. Even though these biomarkers are associated with an increased risk for thromboembolism, they cannot accurately predict future events. In light of this, the use of a scoring system, that would incorporate both circulating biomarkers and clinical factors, might be more useful., Conclusions: Recent research has disclosed several biomarkers as potential predictors of cardioembolic stroke in patients with AF. However, further research is required to establish a multifactorial scoring system that will identify patients at high-risk of thromboembolism, who would benefit from more intensive treatment and monitoring., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Current management of peripheral arterial disease involves risk factor modification and revascularisation, but many patients are still left with debilitating symptoms. Therefore, new treatment strategies are needed. The importance of nitric oxide, and its role in regulating endothelial function, is well-established. Altering the nitric oxide pathway has been extensively studied as a means of treating vascular disease, including peripheral arterial disease. Statins and ACE inhibitors have been shown to enhance endogenous nitric oxide and improve intermittent claudication symptoms. Studies using l-arginine have produced differing results, for reasons for yet fully understood. A greater understanding of the nitric oxide pathway, and its enzymatic control, has generated more potential therapeutic targets to alter NO levels., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Introduction: Arrhythmias can cause symptoms ranging from simple dizziness to life-threatening circulatory collapse. Current management includes medical therapy and procedures such as catheter ablation or device implantation. However, these strategies still pose a risk of serious side effects, and some patients remain symptomatic. Advancement in our understanding of how arrhythmias develop on the cellular level has made more targeted approaches possible. In addition, contemporary studies have found that several genes are involved in the pathogenesis of arrhythmias., Areas Covered: In the present review, the authors explore the cellular and genetic mechanisms leading to arrhythmias as well as the progress that has been made in using both gene and cell therapy to treat tachy- and bradyarrhythmias. They also consider why gene and cell therapy has resulted into a few clinical trials with promising results, however still not applicable in routine clinical practice., Expert Opinion: The question currently is whether such biological therapies could replace current established approaches. The contemporary evidence suggests that despite recent advances in this field, it will need more work in experimental models before this is applied into clinical practice. Gene and cell studies targeting conduction and repolarization are promising, but still not ready for use in the clinical setting.

We have previously generated human IgG1 antibodies that were engineered for reduced binding to the classical Fcγ receptors (FcγRI-III) and C1q, thereby eliminating their destructive effector functions (constant region G1Δnab). In their potential use as blocking agents, favorable binding to the neonatal Fc receptor (FcRn) is important to preserve the long half-life typical of IgG. An ability to cross the placenta, which is also mediated, at least in part, by FcRn is desirable in some indications, such as feto-maternal alloimmune disorders. Here, we show that G1Δnab mutants retain pH-dependent binding to human FcRn but that the amino acid alterations reduce the affinity of the IgG1:FcRn interaction by 2.0-fold and 1.6-fold for the two antibodies investigated. The transport of the modified G1Δnab mutants across monolayers of human cell lines expressing FcRn was approximately 75% of the wild-type, except that no difference was observed with human umbilical vein endothelial cells. G1Δnab mutation also reduced transport in an ex vivo placenta model. In conclusion, we demonstrate that, although the G1Δnab mutations are away from the FcRn-binding site, they have long-distance effects, modulating FcRn binding and transcellular transport. Our findings have implications for the design of therapeutic human IgG with tailored effector functions., (Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Age is an adverse prognostic factor in patients with heart failure. We aimed to assess the impact of age and noncardiac co-morbidities in the outcome of patients undergoing cardiac resynchronization therapy (CRT), and determine which of these two factors is the most important predictor of survival. The study involved a single-center retrospective assessment of 697 consecutive CRT implants during a 12-year period. Patient co-morbidity profile was assessed using the Charlson Co-morbidity Index (CCI) and the Charlson Age-Co-morbidity Index (CACI). Predictors of survival free from heart transplantation were assessed. CRT-related complications and cause of death analysis were assessed within tertiles of the CACI. During a mean follow-up of 1,813 ± 1,177 days, 347 patients (49.9%) died and 37 (5.3%) underwent heart transplantation. On multivariate Cox regression, female gender (HR = 0.78, 95% confidence interval [CI] 0.62 to 0.99, p = 0.041), estimated glomerular filtration rate (HR per ml/min = 0.99, 95% CI 0.98 to 0.99, p < 0.001), left ventricular ejection fraction (HR per % = 0.99, 95% CI 0.98 to 1.00, p = 0.022), New York Heart Association class (HR = 1.83, 95% CI 1.53 to 2.20, p < 0.001), presence of left bundle branch block (HR = 0.70, 95% CI 0.56 to 0.87, p = 0.001), and CACI tertile (HR = 1.37, 95% CI 1.18 to 1.59, p < 0.001) were independent predictors of all-cause mortality or heart transplantation. Compared with age and the CCI, the CACI was the best discriminator of all-cause mortality. Inappropriate therapies occurred less frequently in higher co-morbidity tertiles. In conclusion, patient co-morbidity profile adjusted to age impacts on mortality after CRT implantation. Use of the CACI may help refine guideline criteria to identify patients more likely to benefit from CRT., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Dual-site right ventricular pacing (Dual RV) has been proposed as an alternative for patients with heart failure undergoing cardiac resynchronization therapy (CRT) with a failure to deliver a coronary sinus (CS) lead. Only short-term hemodynamic and echocardiographic results of Dual RV are available. We aimed to assess the long-term results of Dual RV and its impact on survival., Methods: Multicenter retrospective assessment of all CRT implants during a 12-year period. Patients with failed CS lead implantation, treated with Dual RV, were followed and assessed for the primary endpoint of all-cause mortality and/or heart transplant. A control group was obtained from contemporary patients using propensity matching for all available baseline variables., Results: Ninety-three patients were implanted with Dual RV devices and compared with 93 matched controls. During a median of 1,273 days (interquartile range 557-2,218), intention-to-treat analysis showed that all-cause mortality and/or heart transplant was higher in the Dual RV group (adjusted hazard ratio [HR] = 1.66, 95% confidence interval [CI] 1.12-2.47, P = 0.012). As-treated analysis yielded similar results (HR = 1.97, 95% CI 1.31-2.96, P = 0.001). Cardiac device-related infections occurred seven times more frequently in the Dual RV site group (HR = 7.60, 95% CI 1.51-38.33, P = 0.014). Among Dual RV nonresponders, four had their apical leads switched off, five required an epicardial LV lead insertion, a transseptal LV lead was implanted in two, and in nine patients, after reviewing the CS venogram, a new CS lead insertion was successfully attempted., Conclusion: Dual RV pacing is associated with worse clinical outcomes and higher complication rates than conventional CRT., (© 2017 Wiley Periodicals, Inc.)

Distal axon degeneration seen in many peripheral neuropathies is likely to share common molecular mechanisms with Wallerian degeneration. Although several studies in mouse models of peripheral neuropathy showed prevention of axon degeneration in the slow Wallerian degeneration (Wlds) mouse, the role of a recently identified player in Wallerian degeneration, Sarm1, has not been explored extensively. In this study, we show that mice lacking the Sarm1 gene are resistant to distal axonal degeneration in a model of chemotherapy induced peripheral neuropathy caused by paclitaxel and a model of high fat diet induced putative metabolic neuropathy. This study extends the role of Sarm1 to axon degeneration seen in peripheral neuropathies and identifies it as a likely target for therapeutic development., (© 2017 Peripheral Nerve Society.)

Aim: To establish a profile of men in nursing in Western Australia and explore the perception of men in nursing from the perspective of male and female nurses., Background: A project team, including some of the current authors, produced a YouTube video and DVD about men in nursing which led to further enquiry on this topic., Design: The study employed a non-experimental, comparative, descriptive research design focused on a quantitative methodology, using an online survey in early 2014., Method: A convenience sample incorporated registered and enrolled nurses and midwives in Western Australia., Findings: The range of data included demographic information and the respondents' perceptions of men in nursing were collected. Findings indicated that the main reasons for choosing a career in nursing or midwifery were similar for both genders. Common mis-perceptions of men in nursing included: most male nurses are gay; men are not suited to nursing and men are less caring and compassionate than women. Suggestions to promote nursing to men included: nurses are highly skilled professionals; there is the potential to make a difference for patients; nursing offers stable employment, professional diversity and opportunities for team work. There is a diminished awareness of opportunities for men in nursing and negative stereotypes related to men in nursing persist., Conclusion: The study produced recommendations which included: using the right message to target the recruitment for men and promoting a more realistic understanding of the profile and perception of men in nursing., (© 2016 John Wiley & Sons Ltd.)

Lentiviral vectors are widely used in the field of gene therapy as an effective method for permanent gene delivery. While current methods of producing small scale vector batches for research purposes depend largely on culture flasks, the emergence and popularity of lentiviral vectors in translational, preclinical and clinical research has demanded their production on a much larger scale, a task that can be difficult to manage with the numbers of producer cell culture flasks required for large volumes of vector. To generate a large scale, partially closed system method for the manufacturing of clinical grade lentiviral vector suitable for the generation of induced pluripotent stem cells (iPSCs), we developed a method employing a hollow fiber bioreactor traditionally used for cell expansion. We have demonstrated the growth, transfection, and vector-producing capability of 293T producer cells in this system. Vector particle RNA titers after subsequent vector concentration yielded values comparable to lentiviral iPSC induction vector batches produced using traditional culture methods in 225 cm(2) flasks (T225s) and in 10-layer cell factories (CF10s), while yielding a volume nearly 145 times larger than the yield from a T225 flask and nearly three times larger than the yield from a CF10. Employing a closed system hollow fiber bioreactor for vector production offers the possibility of manufacturing large quantities of gene therapy vector while minimizing reagent usage, equipment footprint, and open system manipulation.