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Hitesh C Patel,1 Carl Hayward,1 Vassilis Vassiliou,1 Ketna Patel,2 James P Howard,3 Carlo Di Mario11NIHR Cardiovascular Biomedical Research Unit, Royal Brompton Hospital, London, UK; 2Department of Cardiology, Royal Free Hospital, London, UK; 3National Heart and Lung Institute, Imperial College, London, UKAbstract: Renal sympathetic denervation (RSD) as a therapy for patients with resistant hypertension has attracted great interest. The majority of studies in this field have demonstrated impressive reductions in blood pressure (BP). However, these trials were not randomized or sham-controlled and hence, the findings may have been overinflated due to trial biases. SYMPLICITY HTN-3 was the first randomized controlled trial to use a blinded sham-control and ambulatory BP monitoring. A surprise to many was that this study was neutral. Possible reasons for this neutrality include the fact that RSD may not be effective at lowering BP in man, RSD was not performed adequately due to limited operator experience, patients’ adherence with their antihypertensive drugs may have changed during the trial period, and perhaps the intervention only works in certain subgroups that are yet to be identified. Future studies seeking to demonstrate efficacy of RSD should be designed as randomized blinded sham-controlled trials. The efficacy of RSD is in doubt, but many feel that its safety has been established through the thousands of patients in whom the procedure has been performed. Over 90% of these data, however, are for the Symplicity™ system and rarely extend beyond 12 months of follow-up. Long-term safety cannot be assumed with RSD and nor should it be assumed that if one catheter system is safe then all are. We hope that in the near future, with the benefit of well-designed clinical trials, the role of renal denervation in the management of hypertension will be established.Keywords: resistant hypertension, renal denervation, sympathetic nervous system, symplicity

Aims: One third of patients do not improve after cardiac resynchronization therapy (CRT). Septal flash (SF) and apical rocking (ApRock) are deformation patterns observed on echocardiography in most patients eligible for CRT. These markers of mechanical dyssynchrony have been associated to improved outcome after CRT in observational studies and may be useful to better select patients. The aim of this trial is to investigate whether the current guideline criteria for selecting patients for CRT should be modified and include SF and ApRock to improve therapy success rate, reduce excessive costs and prevent exposure to device-related complications in patients who would not benefit from CRT., Methods: The AMEND-CRT trial is a multicentre, randomized, parallel-group, double-blind, sham-controlled trial with a non-inferiority design. The trial will include 578 patients scheduled for CRT according to the 2021 ESC guidelines who satisfy all inclusion criteria. The randomization is performed 1:1 to an active control arm ('guideline arm') or an experimental arm ('echo arm'). All participants receive a device, but in the echo arm, CRT is activated only when SF or ApRock or both are present. The outcome of both arms will be compared after 1 year. The primary outcome measures are the average change in left ventricular end-systolic volume and patient outcome assessed using a modified Packer Clinical Composite Score., Conclusions: The findings of this trial will redefine the role of echocardiography in CRT and potentially determine which patients with heart failure and a prolonged QRS duration should receive CRT, especially in patients who currently have a class IIa or class IIb recommendation., (© 2024 The Author(s). ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Background  Postoperative surgical site infections are a recognized complication following craniotomies with an associated increase in morbidity and mortality. Several studies have attempted to identify bundles of care to reduce the incidence of infections. Our study aims to clarify which perioperative measures play a role in reducing surgical infection rates further. Methods  This study is a retrospective audit of all elective craniotomies in years 2018 to 2019. The primary endpoint was the surgical site infection rate at 30 days and 4 months after the procedure. Univariate analysis was used to identify factors predictive of postoperative infection. Results  344 patients were included in this study. Postoperative infections were observed in 5.2% of our cohort. No postoperative infections occurred within 4 months in patients receiving perioperative hair wash and intrawound vancomycin powder. In univariate analysis, craniotomy size (Fisher's exact test, p  = 0.05), lack of perioperative hair wash, and vancomycin powder use (Fisher's exact test, p  = 0.01) were predictive of postoperative infection. No complications relative to the use of intrawound vancomycin were observed. Conclusion  Our study demonstrates that simple measures such as perioperative hair wash combined with intrawound vancomycin powder in addition to standard practice can help reducing infection rates with negligible risks and acceptable costs. Our results should be validated further in future prospective studies., Competing Interests: Conflict of Interest None declared., (Asian Congress of Neurological Surgeons. This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. ( https://creativecommons.org/licenses/by-nc-nd/4.0/ ).)

Competing Interests: The authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Background: Endovascular coiling is usually the first line treatment modality for most ruptured intracranial aneurysms. However, there is still some debate as to whether microsurgical clipping or coiling is the treatment of choice for complex wide-necked ruptured middle cerebral artery (MCA) aneurysms. Our aim was to assess the efficacy, safety and longevity of simple endovascular coiling for ruptured MCA aneurysms., Methods: This was a single-centre 10 years retrospective study (2008-2019) of all endovascularly treated patients with ruptured MCA aneurysms ( n = 148). Patients were treated with simple coiling ( n = 111), balloon-assisted coiling ( n = 13), dual micro-catheter coiling ( n = 19), balloon-assisted and dual micro-catheter coiling ( n = 4) and woven endobridge (WEB) device ( n = 1). The standard follow-up protocol consisted of Magnetic Resonance angiography at 6, 12 and 24 months. Our primary endpoints were mortality at 2, 12 and 24 months and dependency at discharge. Secondary endpoints included aneurysm occlusion, complications, re-canalisation, rebleeding and retreatment rates., Results: All-cause mortality at 2, 12 and 24 months was 4.7% ( n = 7), 8.1% ( n = 12) and 10.8% ( n = 16), respectively. 81.3% of patients remained independent in activities of daily livings (ADLs) at the point of discharge. Over a mean follow-up period of 19.7 months, we demonstrated re-bleeding and re-treatment rates of 2.7% ( n = 4) and 4.1% ( n = 6) respectively. Complete occlusion was achieved in 54% ( n = 79) of aneurysms, with recanalisation observed in 18.2% ( n = 27) of the patients., Conclusions: Our results demonstrate that simple endovascular coiling techniques offer a safe and effective solution in the management of ruptured MCA aneurysms without the requirement for re-treatment either surgically or endovascularly using endoluminal stents or other devices.

A simple, straightforward, and energy-efficient greener route for the synthesis of a series of biologically interesting functionalized 1,1-dihomoarylmethane scaffolds has been developed in the presence of meglumine as an efficient and eco-friendly organo-catalyst via one-pot pseudo-three-component reaction at room temperature. Following this protocol, it is possible to synthesize 1,1-dihomoarylmethane scaffolds of an assortment of C-H activated acids such as dimedone, 1,3-cyclohexadione, 4-hydroxy-6-methyl-2-pyrone, 4-hydroxycoumarin, and 1-phenyl-3-methyl-pyrazolone. The salient features of the present green protocol are mild reaction conditions, good to excellent yields, operational simplicity, easy isolation of products, no cumbersome post treatment, high atom economy, and low E-factor. In addition, this chemistry portrays several green advantages including the reusability of reaction media and product scalability, which makes protocol sustainably efficient. Additionally, several control experiments such as protection of catalyst reactive site, D 2 O exchange, and 1 H NMR studies revealed possible pathways for meglumine-promoted reactions. Inspired by the natural physiological environment of 1,1-dihomoarylmethane scaffolds, we reconnoitered the biological profile of our compounds and synthesized compounds that were promising for their antiproliferative and antibacterial activities., Competing Interests: The authors declare no competing financial interest., (© 2022 The Authors. Published by American Chemical Society.)

Background: Intracerebral haemorrhage (ICH) accounts for 10%-15% of strokes in the UK, but is responsible for half of all annual global stroke deaths. The ABC bundle for ICH was developed and implemented at Salford Royal Hospital, and was associated with a 44% reduction in 30-day case fatality. Implementation of the bundle was scaled out to the other hyperacute stroke units (HASUs) in the region from April 2017. A mixed methods evaluation was conducted alongside to investigate factors influencing implementation of the bundle across new settings, in order to provide lessons for future spread., Methods: A harmonised quality improvement registry at each HASU captured consecutive patients with spontaneous ICH from October 2016 to March 2018 to capture process and outcome measures for preimplementation (October 2016 to March 2017) and implementation (April 2017 to March 2018) time periods. Statistical analyses were performed to determine differences in process measures and outcomes before and during implementation. Multiple qualitative methods (interviews, non-participant observation and project document analysis) captured how the bundle was implemented across the HASUs., Results: HASU1 significantly reduced median anticoagulant reversal door-to-needle time from 132 min (IQR: 117-342) preimplementation to 76 min (64-113.5) after implementation and intensive blood pressure lowering door to target time from 345 min (204-866) preimplementation to 84 min (60-117) after implementation. No statistically significant improvements in process targets were observed at HASU2. No significant change was seen in 30-day mortality at either HASU. Qualitative evaluation identified the importance of facilitation during implementation and identified how contextual changes over time impacted on implementation. This identified the need for continued implementation support., Conclusion: The findings show how the ABC bundle can be successfully implemented into new settings and how challenges can impede implementation. Findings have been used to develop an implementation strategy to support future roll out of the bundle outside the region., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Wavelet transforms of an image result in set of wavelet coefficients. Thresholding eliminates insignificant coefficients while retaining the significant ones (resulting in matrix having few nonzero elements that need to be stored). The compressed image is reconstructed by applying inverse wavelet transform. The quality of compressed image deteriorates with increase in compression. Hence, finding optimum value of scale and threshold is a challenging task. The objective of the study was to find the optimum value of scale and threshold for compressing 99mTc-methylene diphosphonate (99 mTc-MDP) bone scan images using Haar wavelet transform., Materials and Methods: Haar wavelet transform at scale 1-8 was applied on 106 99 mTc-MDP whole-body bone scan images, and wavelet coefficients were threshold at 90, 95, 97, and 99 percentiles, followed by inverse wavelet transform to get 3392 compressed images. Nuclear medicine physician (NMP) compared compressed image with its corresponding input to label it as acceptable or unacceptable. The values of scale and threshold that resulted in majority of acceptable images were considered to be optimum. The quality of compressed image was also evaluated using perception image quality evaluator (PIQE) image quality metrics. Compression ratio was calculated by dividing the number of nonzero elements after thresholding wavelet coefficients by the number of nonzero elements in Haar decomposed matrix., Results: NMP found quality of compressed images (obtained at scale 2 and 90 percentile threshold) identical to the quality of the corresponding input images. As per PIQE score, quality of compressed images was perceptually better than that of the corresponding input images., Conclusions: The optimum values of scale and threshold were determined to be 2 and 90 percentiles, respectively., Competing Interests: There are no conflicts of interest., (Copyright: © 2022 Indian Journal of Nuclear Medicine.)

Mild traumatic brain injury (mild TBI), often referred to as concussion, is the most common form of TBI and affects millions of people each year. A history of mild TBI increases the risk of developing emotional and neurocognitive disorders later in life that can impact on day to day living. These include anxiety and depression, as well as neurodegenerative conditions such as chronic traumatic encephalopathy (CTE) and Alzheimer's disease (AD). Actions of brain resident or peripherally recruited immune cells are proposed to be key regulators across these diseases and mood disorders. Here, we will assess the impact of mild TBI on brain and patient health, and evaluate the recent evidence for immune cell involvement in its pathogenesis., Competing Interests: The 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 © 2021 Verboon, Patel and Greenhalgh.)

Implementation of an acute bundle of care for intracerebral haemorrhage (ICH) was associated with a marked improvement in survival at our centre, mediated by a reduction in early (<24 hours) do-not-resuscitate (DNR) orders. The aim of this study was to identify possible mechanisms for this mediation. We retrospectively extracted additional data on resuscitation attempts and supportive care. This observational study utilised existing data collected for the Acute Bundle of Care for ICH (ABC-ICH) quality improvement project between from 2013 to 2017. The primary outcome was whether a patient received an early (<24 hours) DNR order. We used multivariable logistic regression to estimate the adjusted association between clinically meaningful factors, including an indicator for a change in treatment on the introduction of the ABC care bundle. Early DNR orders were associated with a reduced odds of escalation to critical care (OR: 0.07, 95% CI: 0.03 to 0.17, p<0.001). Commencement of palliative care within 72 hours was far more likely (OR: 8.76, 95% CI: 4.74 to 16.61, p<0.001) if an early DNR was in place. The cardiac arrest team were not called for an ICH patient before implementation but were called on five occasions overall during and after implementation. Further qualitative evaluation revealed that on only one occasion was there a cardiac or respiratory arrest with cardiopulmonary resuscitation performed. We found no significant increase in resuscitation attempts after bundle implementation but early DNR orders were associated with less admission to critical care and more early palliation. Early DNR orders are associated with less aggressive supportive care and should be judiciously used in acute ICH., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.)

Background: There is a disparity between the number of interventional neuroradiologists (INRs) in the UK and the number needed to provide a comprehensive 24/7 interventional neurovascular service. It is recognized that trainees from other specialties such as neurosurgery may be able to provide INR services after appropriate training. At present gaining skills in INR is not a mandatory requirement of the neurosurgical training curriculum in the UK. The views on this issue of current neurosurgical trainees are unknown. We aimed to address this knowledge gap., Methods: We performed an anonymized online survey to gauge the opinion of neurosurgical trainees about their attitudes to INR training and service provision., Results: 90/265 (34%) UK neurosurgical trainees responded to the survey. About 56% of respondents reported they were likely or very likely to pursue interventional training if a curriculum was approved by the general medical council. About 80% thought training should take up to 2 years. About 90% of those very likely or likely to pursue INR wanted a hybrid neurosurgical practice and 92% were willing to provide endovascular services out of hours., Conclusion: The responses described suggest that a significant proportion of neurosurgical trainees would pursue INR training and have realistic expectation regarding out of hours commitment and length of training., Competing Interests: There are no conflicts of interest., (Copyright: © 2020 Surgical Neurology International.)

Objectives: Being able to predict which patients with COVID-19 are going to deteriorate is important to help identify patients for clinical and research practice. Clinical prediction models play a critical role in this process, but current models are of limited value because they are typically restricted to baseline predictors and do not always use contemporary statistical methods. We sought to explore the benefits of incorporating dynamic changes in routinely measured biomarkers, non-linear effects and applying 'state-of-the-art' statistical methods in the development of a prognostic model to predict death in hospitalised patients with COVID-19., Design: The data were analysed from admissions with COVID-19 to three hospital sites. Exploratory data analysis included a graphical approach to partial correlations. Dynamic biomarkers were considered up to 5 days following admission rather than depending solely on baseline or single time-point data. Marked departures from linear effects of covariates were identified by employing smoothing splines within a generalised additive modelling framework., Setting: 3 secondary and tertiary level centres in Greater Manchester, the UK., Participants: 392 hospitalised patients with a diagnosis of COVID-19., Results: 392 patients with a COVID-19 diagnosis were identified. Area under the receiver operating characteristic curve increased from 0.73 using admission data alone to 0.75 when also considering results of baseline blood samples and to 0.83 when considering dynamic values of routinely collected markers. There was clear non-linearity in the association of age with patient outcome., Conclusions: This study shows that clinical prediction models to predict death in hospitalised patients with COVID-19 can be improved by taking into account both non-linear effects in covariates such as age and dynamic changes in values of biomarkers., Competing Interests: Competing interests: Swedish Orphan Biovitrum have provided investigational medicinal product for public-funded, peer-reviewed trials on which AK, AV, JG, HCP and SH are coinvestigators. The other authors declare no competing interests., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ.)

Background: Elevated left atrial (LA) pressure, particularly during exercise, is associated with symptomatic status and survival in patients with heart failure with preserved ejection fraction (HFpEF). We aimed to characterize the contribution of abnormal LA mechanical properties to exercise haemodynamics in HFpEF., Methods and Results: Simultaneous echocardiography and right heart catheterization were performed in 71 subjects with left ventricular ejection fraction ≥ 50% referred for assessment of exertional dyspnoea. According to haemodynamic evaluation, 49 patients were diagnosed with HFpEF [pulmonary capillary wedge pressure (PCWP) ≥ 15 mmHg at rest and/or ≥ 25 mmHg at maximal exertion] and 22 as non-cardiac dyspnoea. Apical two- and four-chamber views were used for blinded two-dimensional LA speckle tracking analysis. HFpEF was characterized by impaired LA reservoir (24.3 ± 9.6 vs. 36.7 ± 8.4%, P < 0.001) and pump strain (-11.5 ± 3.2 vs. -17.0 ± 3.4%, P < 0.001); and increased stiffness (0.8 ± 0.7 vs. 0.2 ± 0.1 mmHg/%, P < 0.001). Reservoir and pump strain correlated with exercise PCWP (r = -0.64 and r = 0.72, P < 0.001), and remained independent predictors after adjusting for left ventricular mass index, LA volume index, mean E/e' and systolic blood pressure (B = -0.66 and B = 1.41, respectively, P < 0.001). LA stiffness was strongly related to B-type natriuretic peptide levels (r = 0.73, P < 0.001; B = 173.0, P < 0.001). Reservoir strain at cut-off of ≤ 33% predicted invasively verified HFpEF diagnosis with 88% sensitivity and 77% specificity, providing a net reclassification improvement of 12% in comparison to the 2016 European Society of Cardiology criteria for non-invasive diagnosis of HFpEF., Conclusions: Impaired LA reservoir and pump function and increased stiffness are associated with abnormal exercise haemodynamics in HFpEF. These markers provide significant HFpEF diagnostic utility in elderly ambulatory patients with dyspnoea., (© 2019 The Authors. European Journal of Heart Failure © 2019 European Society of Cardiology.)

Background: Heart rate variability (HRV) analysis is uncommonly undertaken in patients with atrial fibrillation (AF) due to an assumption that ventricular response is random. We sought to determine the effects of head-up tilt (HUT), a stimulus known to elicit an autonomic response, on HRV in patients with AF; we contrasted the findings with those of patients in sinus rhythm (SR)., Methods: Consecutive, clinically indicated tilt tests were examined for 207 patients: 176 in SR, 31 in AF. Patients in AF were compared to an age-matched SR cohort (n = 69). Five minute windows immediately before and after tilting were analyzed using time-domain, frequency-domain and nonlinear HRV parameters. Continuous, noninvasive assessment of blood pressure, heart rate and stroke volume were available in the majority of patients., Results: There were significant differences at baseline in all HRV parameters between AF and age matched SR. HUT produced significant hemodynamic changes, regardless of cardiac rhythm. Coincident with these hemodynamic changes, patients in AF had a significant increase in median [quartile 1, 2] DFA-α2 (+0.14 [-0.03, 0.32], p < .005) and a decrease in sample entropy (-0.17 [-0.50, -0.01], p < .005)., Conclusion: In the SR cohort, increasing age was associated with fewer HRV changes on tilting. Patients with AF had blunted HRV responses to tilting, mirroring those seen in an age matched SR group. It is feasible to measure HRV in patients with AF and the changes observed on HUT are comparable to those seen in patients in sinus rhythm., (© 2017 Wiley Periodicals, Inc.)

Heart failure with preserved ejection fraction (HFpEF) represents a heterogeneous collection of conditions that are unified by the presence of a left ventricular ejection fraction ≥50%, evidence of impaired diastolic function and elevated natriuretic peptide levels, all within the context of typical heart failure signs and symptoms. However, while HFpEF is steadily becoming the predominant form of heart failure, disease-modifying treatment options for this population remain sparse. This review provides an overview of the diagnosis, management and prevention of HFpEF for general physicians., (© Royal College of Physicians 2018. All rights reserved.)

Heart failure is highly prevalent with more than 50% of cases being patients with a preserved ejection fraction (HFPEF), a figure that is projected to increase due to the changing risk factor landscape, in particular the ageing population. Overall mortality is similar to patients with heart failure with reduced ejection fraction (HFREF), as are the rates of hospitalisation. Patients with HFPEF have more comorbid conditions with fewer therapeutic options available. In this review, we explore the epidemiology of hospitalisation of HFPEF, the impact of current treatment modalities, and the potential of future therapies., Competing Interests: Declaration of conflicting interests:The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Despite improvements in medical therapy and device-based treatment, heart failure (HF) continues to impose enormous burdens on patients and health care systems worldwide. Alterations in autonomic nervous system (ANS) activity contribute to cardiac disease progression, and the recent development of invasive techniques and electrical stimulation devices has opened new avenues for specific targeting of the sympathetic and parasympathetic branches of the ANS. The Heart Failure Association of the European Society of Cardiology recently organized an expert workshop which brought together clinicians, trialists and basic scientists to discuss the ANS as a therapeutic target in HF. The questions addressed were: (i) What are the abnormalities of ANS in HF patients? (ii) What methods are available to measure autonomic dysfunction? (iii) What therapeutic interventions are available to target the ANS in patients with HF, and what are their specific strengths and weaknesses? (iv) What have we learned from previous ANS trials? (v) How should we proceed in the future?, (© 2017 The Authors. European Journal of Heart Failure © 2017 European Society of Cardiology.)

Background and Purpose: The mortality and morbidity after aneurysmal subarachnoid hemorrhage has improved because of better diagnosis, early treatment to secure the aneurysm, and better management of disease-specific complications. With these improvements in care, it is not clear if the previously identified independent predictors of a negative outcome have changed. The aim of this study was to identify the independent predictors of an unfavorable outcome (Glasgow Outcome Score 1, 2, and 3) in aneurysmal subarachnoid hemorrhage patients., Methods: Univariate and multivariate analysis of prospectively collected data on patients presenting with an aneurysmal subarachnoid hemorrhage was performed. Outcome was assessed at discharge. Data were collected from 14 centers in the United Kingdom over a period of 4 years (September 2011-2015)., Results: The median age (interquartile range) at presentation of 3341 patients with aneurysmal subarachnoid hemorrhage was 55 (18) years. Most patients were female (n=2288 [68.5%]), presented in good grade (2397 [70%]; World Federation of Neurological Surgeons grade 1 and 2), and were treated by endovascular coiling (n=2600; 75%). The independent predictors of an unfavorable outcome (95% confidence interval [CI]) were increasing age (odds ratio [OR], 1.04; 95% CI, 1.03-1.05; P <0.001), World Federation of Neurological Surgeons grade (OR, 2.06; 95% CI, 1.91-2.22; P <0.001), preoperative rebleeding (OR, 7.41; 95% CI, 4.48-12.30; P <0.001), need for cerebrospinal fluid diversion (OR, 3.25; 95% CI, 2.58-4.09; P <0.001), and delayed cerebral ischemia (OR, 2.21; 95% CI, 1.72-2.83; P <0.001)., Conclusions: These data suggest that potentially modifiable risk factors of preoperative rebleeding and delayed cerebral ischemia are associated with unfavorable outcomes. Understanding the reasons why patients requiring cerebrospinal fluid diversion have 3.25-fold higher adjusted odds of a poor outcome at discharge needs to be studied., (© 2017 American Heart Association, Inc.)

We describe a technique that uses both posterior-anterior and caudal fluoroscopy to achieve venous access for pacemaker device implantation. A significant advantage of this technique is the ability to clearly demarcate both the anatomy of venous drainage and the lung border. We would encourage all centres to adopt this technique as a safe approach to venous access., Competing Interests: Competing interests: None declared.

Objective: To assess the effect of renal denervation (RDT) on micro- and macro-vascular function in patients with heart failure with preserved ejection fraction (HFpEF)., Design: A prospective, randomised, open-controlled trial with blinded end-point analysis., Setting: A single-centre London teaching hospital., Participants: Twenty-five patients with HFpEF who were recruited into the RDT-PEF trial., Main Outcome Measures: Macro-vascular: 24-h ambulatory pulse pressure, aorta distensibilty (from cardiac magnetic resonance imaging (CMR), aorta pulse wave velocity (CMR), augmentation index (peripheral tonometry) and renal artery blood flow indices (renal MR). Micro-vascular: endothelial function (peripheral tonometry) and urine microalbuminuria., Results: At baseline, 15 patients were normotensive, 9 were hypertensive and 1 was hypotensive. RDT did not lower any of the blood pressure indices. Though there was evidence of abnormal vascular function at rest, RDT did not affect these at 3 or 12 months follow-up., Conclusions: RDT did not improve markers of macro- and micro-vascular function.

Importance  Effective preoperative antisepsis is recognized to prevent surgical site infection (SSI), although the definitive method is unclear. Many have compared chlorhexidine (CHG) with povidone-iodine (PVI), but there is emerging evidence for combination usage. Objective  To conduct a systematic review and meta-analysis to evaluate if combination skin preparation (1) reduces colonization at the operative site and (2) prevents SSI compared with single-agent use. Data Sources  A literature search of MEDLINE, Embase, and Cochrane Database of Clinical Trials was performed. Study Selection  Comparative, human trials considering the combination use of CHG and PVI, as preoperative antisepsis, to single-agent CHG or PVI use were included. Studies were excluded from meta-analysis if the use or absence of alcohol was inconsistent between study arms. Data Extraction and Synthesis  The study was performed using PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. Main Outcomes and Measures  The primary outcome for meta-analysis was surgical site infection. The secondary outcome was colonization at the operative site. Results  Eighteen publications with a combination of CHG and PVI use were identified. Of these, 12/14 inferred promise for combination usage, including four trials eligible for meta-analysis. Only one trial reported SSI as its outcome. The remaining three considered bacterial colonization. Combination preparation had a pooled odds ratio for complete decolonization of 5.62 (95% confidence interval 3.2 to 9.7, p  < 0.00001). There was no evidence of heterogeneity (Cochran's Q 2.1, 2 df , p  = 0.35). Conclusions and Relevance  There is emerging, albeit low-quality, evidence in favor of combination CHG and PVI preoperative antisepsis. Further rigorous investigation is indicated.

Aim: Heart failure with preserved ejection fraction (HFpEF) is associated with increased sympathetic nervous system (SNS) tone. Attenuating the SNS with renal denervation (RDT) might be helpful and there are no data currently in humans with HFpEF., Methods and Results: In this single-centre, randomized, open-controlled study we included 25 patients with HFpEF [preserved left ventricular (LV) ejection fraction, left atrial (LA) dilatation or LV hypertrophy and raised B-type natriuretic peptide (BNP) or echocardiographic assessment of filling pressures]. Patients were randomized (2:1) to RDT with the Symplicity™ catheter or continuing medical therapy. The primary success criterion was not met in that there were no differences between groups at 12 months for Minnesota Living with Heart Failure Questionnaire score, peak oxygen uptake (VO2 ) on exercise, BNP, E/e', LA volume index or LV mass index. A greater proportion of patients improved at 3 months in the RDT group with respect to VO2 peak (56% vs. 13%, P = 0.025) and E/e' (31% vs. 13%, P = 0.04). Change in estimated glomerular filtration rate was comparable between groups. Two patients required plain balloon angioplasty during the RDT procedure to treat renal artery wall oedema., Conclusion: This study was terminated early because of difficulties in recruitment and was underpowered to detect whether RD improved the endpoints of quality of life, exercise function, biomarkers, and left heart remodelling. The procedure was safe in patients with HFpEF, although two patients did require intraprocedure renal artery dilatation., (© 2016 The Authors European Journal of Heart Failure © 2016 European Society of Cardiology.)

Objectives: Low back pain (LBP), from degenerative lumbar spine disease, represents a significant burden on healthcare resources. Studies worldwide report trends attributable to their country's specific demographics and healthcare system. Considering England's specific medico-socioeconomic conditions, we investigate recent trends in hospital admissions and procedures for LBP, and discuss the implications for the allocation of healthcare resources., Design: Retrospective cohort study using Hospital Episode Statistics data relating to degenerative lumbar spine disease in England, between 1999 and 2013. Regression models were used to analyse trends., Outcome Measures: Trends in the number of admissions and procedures for LBP, mean patient age, gender and length of stay., Results: Hospital admissions and procedures have increased significantly over the study period, from 127.09 to 216.16 and from 24.5 to 48.83 per 100,000, respectively, (p<0.001). The increase was most marked in the oldest age groups with a 1.9 and 2.33-fold increase in admissions for patients aged 60-74 and ≥ 75 years, respectively, and a 2.8-fold increase in procedures for those aged ≥ 60 years. Trends in hospital admissions were characterised by a widening gender gap, increasing mean patient age, and decreasing mean hospital stay (p<0.001). Trends in procedures were characterised by a narrowing gender gap, increasing mean patient age (p=0.014) and decreasing mean hospital stay (p<0.001). Linear regression models estimate that each hospital admission translates to 0.27 procedures, per 100,000 (95% CI 0.25 to 0.30, r 0.99, p<0.001; r, Pearson's correlation coefficient). Hospital admissions are increasing at 3.5 times the rate of surgical procedures (regression gradient 7.63 vs 2.18 per 100,000/year)., Conclusions: LBP represents a significant and increasing workload for hospitals in England. These trends demonstrate an increasing demand for specialists involved in the surgical and non-surgical management of this disease, and highlight the need for services capable of dealing with the increased comorbidity burden associated with an ageing patient group., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

Background: Qualitative and quantitative assessment of renal blood flow is valuable in the evaluation of patients with renal and renovascular diseases as well as in patients with heart failure. The temporal pattern of renal flow velocity through the cardiac cycle provides important information about renal haemodynamics. High temporal resolution interleaved spiral phase velocity mapping could potentially be used to study temporal patterns of flow and measure resistive and pulsatility indices which are measures of downstream resistance., Methods: A retrospectively gated breath-hold spiral phase velocity mapping sequence (TR 19 ms) was developed at 3 Tesla. Phase velocity maps were acquired in the proximal right and left arteries of 10 healthy subjects in each of two separate scanning sessions. Each acquisition was analysed by two independent observers who calculated the resistive index (RI), the pulsatility index (PI), the mean flow velocity and the renal artery blood flow (RABF). Inter-study and inter-observer reproducibility of each variable was determined as the mean +/- standard deviation of the differences between paired values. The effect of background phase errors on each parameter was investigated., Results: RI, PI, mean velocity and RABF per kidney were 0.71+/- 0.06, 1.47 +/- 0.29, 253.5 +/- 65.2 mm/s and 413 +/- 122 ml/min respectively. The inter-study reproducibilities were: RI -0.00 +/- 0.04 , PI -0.03 +/- 0.17, mean velocity -6.7 +/- 31.1 mm/s and RABF per kidney 17.9 +/- 44.8 ml/min. The effect of background phase errors was negligible (<2% for each parameter)., Conclusions: High temporal resolution breath-hold spiral phase velocity mapping allows reproducible assessment of renal pulsatility indices and RABF.

Early phase studies of novel interventions for hypertension, such as renal sympathetic denervation, are sometimes single-armed (uncontrolled). We explored the wisdom of this by quantifying the blood pressure fall in the placebo arms of contemporary trials of hypertension. We searched Medline up to June 2014 and identified blinded, randomized trials of hypertension therapy in which the control arm received placebo medication or a sham (placebo) procedure. For nonresistant hypertension, we have identified all such trials of drugs licensed by the US Food and Drug Administration since 2000 (5 drugs). This US Food and Drug Administration-related restriction was not applied to resistant hypertension trials. This produced 7451 patients, who were allocated to a blinded control from 52 trials of nonresistant hypertension and 694 patients from 8 trials of resistant hypertension (3 drugs and 2 interventions). Systolic blood pressure fell by 5.92 mm Hg (95% confidence interval, 5.14-6.71; P<0.0001) in the nonresistant cohort and by 8.76 mm Hg (95% confidence interval, 4.83-12.70; P<0.0001) in the resistant cohort. Using metaregression, the falls were larger in trials that did not use ambulatory blood pressure monitoring as an inclusion criterion (z=2.84; P=0.0045), in those with higher baseline blood pressures (z=-0.3; P=0.0001), and in those where the patients were prescribed a continuous background of antihypertensives (z=-2.72; P=0.0065). The nontrivial magnitude of these apparent blood pressure reductions with perfectly ineffective intervention (placebo) illustrates that efficacy explorations of novel therapies for hypertension, once safety is established, should be performed with a randomized, appropriately controlled, and blinded design., (© 2014 American Heart Association, Inc.)

Aims: To determine the impact of internationally recognized criteria for the diagnosis of heart failure with preserved ejection fraction (HF-PEF) on the feasibility of recruitment into a HF-PEF trial., Methods and Results: We reviewed the medical records of 5883 consecutive patients admitted with heart failure across eight hospitals in the U.K. From those who had an EF ≥50% (filter 1), patients who had an alternative cardiac cause of symptoms or an over-riding co-morbidity were excluded (filter 2). The remaining patients had to satisfy the following selection criteria (filter 3): the presence of a non-dilated left ventricle; structural remodelling (LV hypertrophy or dilated left atrium); and evidence of impaired diastolic function or raised BNP. Overall, 20.5% (n = 1203) of patients admitted with heart failure had an EF ≥50%. There was significant heterogeneity between the hospitals as this proportion varied from 42.4% in the teaching hospitals to 13.8% in the district general hospitals (P < 0.0001). Applying filter 2, the cohort size was reduced from 1203 to 122 patients. Of the latter 122, only 45 people had evidence of structural cardiac remodelling and evidence of either raised cardiac filling pressures on echocardiography or raised BNP consistent with HF-PEF., Conclusion: Applying our filters, only 0.8% of all patients admitted with heart failure would be eligible for a HF-PEF trial. These data have important implications for the feasibility of clinical trials for HF-PEF and for the generalizability of the results of such studies., (© 2014 The Authors. European Journal of Heart Failure © 2014 European Society of Cardiology.)

Resistant hypertension is, by definition, a challenge to most physicians treating hypertension. Renal sympathetic denervation has shown promising early results in treating this condition. The SYMPLICITY HTN-3 is the most recent trial to report the effects of this technique on resistant hypertension. This review discusses this study and its surprising neutral results before ending with an overview of key lessons learned.

Objectives: To identify factors associated with the decision to transfer and/or operate on patients with intracerebral haemorrhage (ICH) at a UK regional neurosurgical centre and test whether these decisions were associated with patient survival., Design: Retrospective cohort study., Setting: 14 acute and specialist hospitals served by the neurosurgical unit at Salford Royal NHS Foundation Trust, Salford, UK., Participants: All patients referred acutely to neurosurgery from January 2008 to October 2010., Outcome Measures: Primary outcome was survival and secondary outcomes were transfer to the neurosurgical centre and acute neurosurgery., Results: We obtained clinical data from 1364 consecutive spontaneous patients with ICH and 1175 cases were included in the final analysis. 140 (12%) patients were transferred and 75 (6%) had surgery. In a multifactorial analysis, the decision to transfer was more likely with younger age, women, brainstem and cerebellar location and larger haematomas. Risk of death in the following year was higher with advancing age, lower Glasgow Coma Scale, larger haematomas, brainstem ICH and intraventricular haemorrhage. The transferred patients had a lower risk of death relative to those remaining at the referring centre whether they had surgery (HR 0.46, 95% CI 0.32 to 0.67) or not (HR 0.41, 95% CI 0.22 to 0.73). Acute management decisions were included in the regression model for the 227 patients under either stroke medicine or neurosurgery at the neurosurgical centre and early do-not-resuscitate orders accounted for much of the observed difference, independently associated with an increased risk of death (HR 4.8, 95% CI 2.7 to 8.6)., Conclusions: The clear association between transfer to a specialist centre and survival, independent of established prognostic factors, suggests aggressive supportive care at a specialist centre may improve survival in ICH and warrants further investigation in prospective studies.

Background and Purpose: Various grading scores to predict survival after intracerebral hemorrhage (ICH) have been described. We aimed to test the accuracy and clinical usefulness of 3 well-known scores (original ICH score, modified ICH score, and ICH grading scale) in a large unselected cohort of typical ICH patients., Methods: A total of 1364 ICH cases were referred to our center from January 1, 2008, to October 17, 2010. Clinical details were prospectively recorded, and the first computed tomography brain scan was retrospectively reviewed to determine ICH volume and location and to identify intraventricular hemorrhage. The original ICH, ICH grading scale, and modified ICH score were calculated. Receiver operating characteristic and decision curves for 30-day mortality were generated., Results: A total of 1175 patients were included in the final analysis. All 3 scores and the Glasgow Coma Scale (GCS) divided cases into groups with highly significant differences in mortality. The area under the receiver operating characteristic curve was very similar for original ICH (0.861), ICH grading scale (0.874), and GCS (0.872), but was less for modified ICH score (0.824). Age was much less predictive (0.565). Combining GCS with age, log ICH volume, and intraventricular hemorrhage to derive a multifactorial risk of death at 30 days significantly increased the area under the receiver operating characteristic curve (0.897). All scores and GCS demonstrated a similar net benefit for threshold probabilities of 10% to 95%. Above 95%, the net benefit of GCS became inferior to the prognostic scores., Conclusions: Although existing grading scores are highly predictive of 30-day mortality, GCS alone was as predictive in our cohort, but age was not.

Background: Historically neurosurgeons have accepted head injured patients only in the presence of a mass lesion requiring surgical decompression. Underpinning this is an assumption that these patients have a better outcome than patients without a surgical lesion. This has meant that many patients without a surgical lesion have been managed locally in the referring hospital. However, there is now evidence that treatment of all head injured patients in a specialist centre leads to improved outcomes. Therefore, we have asked the question: does the presence of a surgical lesion imply better outcome from severe head injury?, Results: We prospectively recorded the Glasgow Outcome score (GOS), at 3 months, of all the severely head injured patients treated at our institution over a two and a half year period. Of 116 patients admitted with an initial Glasgow Coma Score (GCS) of 8 or less, 58 had surgical lesions and 58 non-surgical head injuries. The two groups were well matched for presenting GCS and age. Overall our favourable outcome rate (GOS 4 and 5) at 3-months for the patients with a surgical lesion and for the non-surgical group were 47.3% and 46.6% respectively, with no significant difference between the two (P = 0.54)., Conclusion: The assumption in the past has always been that patients presenting in coma from traumatic diffuse brain injury will do worse than those that have a mass lesion amenable to surgical decompression. Our series would suggest that this is not the case and all severely head injured patients should expect similar outcome when cared for in a neuroscience centre.

The aim of this study was to assess the prevalence of otological symptoms in patients with chlamydial conjunctivitis. We report four cases of chlamydial conjunctivitis, in association with otitis media, that were investigated by an otologist.

alphaA-crystallin is a small heat-shock protein expressed preferentially in the lens and is detected during the early stages of lens development. Recent work indicates that the expression of alphaA-crystallin enhances lens epithelial cell growth and resistance to stress conditions. Mutation of the arginine 116 residue to cysteine (R116C) in alphaA-crystallin has been associated with congenital cataracts in humans. However, the physiological consequences of this mutation have not been analyzed in lens epithelial cells. In the present study, we expressed wild type or R116C alphaA-crystallin in the human lens epithelial cell line HLE B-3. Immunofluorescence and confocal microscopy indicated that both wild type and R116C alphaA-crystallin were distributed mainly in the cytoplasm of lens epithelial cells. Size-exclusion chromatography indicated that the size of the alphaA-crystallin aggregate in lens epithelial cells increased from 500 to 600 kDa for the wild type protein to >2 MDa in the R116C mutant. When cells were exposed to physiological levels of UVA radiation, wild type alphaA-crystallin protected cells from apoptotic death as shown by annexin labeling and flow cytometric analysis, whereas the R116C mutant had a 4- to 10-fold lower protective ability. UVA-irradiated cells expressing the wild type protein had very low TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling) staining, whereas cells expressing R116C mutant had a high level of TUNEL staining. F-actin was protected in UVA-treated cells expressing the wild type alphaA-crystallin but was either clumped around the apoptotic cells or was absent in apoptotic cells in cultures expressing the R116C mutant. Structural changes caused by the R116C mutation could be responsible for the reduced ability of the mutant to protect cells from stress. Our study shows that comparing the stress-induced apoptotic cell death is an effective way to compare the protective abilities of wild type and mutant alphaA-crystallin. We propose that the diminished protective ability of the R116C mutant in lens epithelial cells may contribute to the pathogenesis of cataract.

There are several lines of evidence clearly demonstrating that major histocompatibility complex (MHC) class I antigens are important in protecting haemopoietic tumour cells from natural killer (NK)-mediated cell lysis. In the present studies we examined the role of MHC class II antigens in affording such protection to haemopoietic tumour cell lines. NK and lymphokine-activated killer (LAK) lysis were performed on two human B lymphoma cell lines and their mutants lacking HLA class II expression, i.e. DR, DP and DQ. Raji and T5-1 were compared to their mutants RM3 and 6.1.6, respectively. Significantly more lysis was observed with the mutants compared to the parent cell line. Effectors used included (1) peripheral blood NK effectors, (2) a human NK cell line (NK 3.3), and (3) peripheral blood LAK effectors. The increased lysis with the mutants could not be explained on the basis of (1) increased conjugate formation, (2) increased cell fragility or (3) ineffectual expression of HLA class I and other non-HLA antigens. These findings suggest that HLA class II molecules may have a novel role. They may be relevant not only in antigen presentation but may also protect tumour cells (and possibly normal activated lymphoid cells) against lysis mediated by NK and LAK cells.

Fungal (Penicillium chrysogenum) and yeast (Saccharomyces cerevisiae) ATP sulfurylases were shown to have very similar kinetic and chemical properties except that the fungal enzyme (a) contains a highly reactive Cys residue (SH-1) whose modification results in sigmoidal velocity curves (Renosto, F., Martin, R. L., and Segel, I. H. (1987) J. Biol. Chem. 262, 16279-16288) and (b) is allosterically inhibited by 3'-phosphoadenosine 5'-phosphosulfate (PAPS), while the yeast enzyme displays neither of these properties. The fungal enzyme subunit (64.3 kDa, 572 amino acids) is also larger than the yeast enzyme subunit (59.3 kDa, 521 amino acids). To correlate the unique allosteric properties of the fungal enzyme with specific structural features, we cloned and sequenced the ATP sulfurylase gene (aps) from P. chrysogenum. The yeast and fungal enzymes are homologous over the first 400 amino acids and contain two regions high in basic residues which are conserved in sulfurylases from Arabidopsis and the Riftia pachyptila (hydrothermal vent tube worm) chemolithotrophic symbiont. These regions may participate in forming the binding sites for MgATP2- and SO4(2-). The fungal enzyme has no sites for MgATP2- and SO4(2-). The fungal enzyme has no significant sequence homology to the yeast enzyme in the C-terminal 172 amino acids. This C-terminal region contains SH-1 (Cys-508) and has homology to MET14 (S. cerevisiae), CYSC (E. coli), and NODQ (Rhizobium meliloti), i.e. adenosine 5'-phosphosulfate (APS) kinase. The cumulative results suggest that (a) the allosteric PAPS binding site of P. chrysogenum ATP sulfurylase is located in the C-terminal domain of the protein and (b) that this domain may have evolved from APS kinase. In spite of the homology, this C-terminal region does not account for the APS kinase activity of P. chrysogenum. Fungal ATP sulfurylase has no significant homology to (or regulatory properties in common with) CYSD or CYSN, proteins reported to comprise E. coli ATP sulfurylase (Leyh, T., Vogt, T. F., and Suo, Y. (1992) J. Biol. Chem. 267, 10405-10410).

Addition of biotin to culture medium NL-406 significantly increased alkaloid yield during submerged cultivation of Claviceps sp. strain SD-58. Alkaloid yield was further enhanced by incorporating leucine in biotin-supplemented culture medium. Increased alkaloid production was associated with an increase in the lipid content of cells and in the number of chlamydospores. Biotin deficiency caused a reduction in alkaloid yield and a parallel decrease in lipid content and chlamydospore numbers.