Search

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

Background: Ventriculomegaly is common in aneurysmal subarachnoid haemorrhage (aSAH). An imaging measure to predict the need for cerebrospinal fluid (CSF) diversion may be useful. The bicaudate index (BCI) has been previously applied to aSAH. Our aim was to derive and test a threshold BCI above which CSF diversion may be required., Methods: Review of prospective registry. The derivation group (2009-2015) included WFNS grade 1-2 aSAH patients who deteriorated clinically, had a repeat CT brain and underwent CSF diversion. BCI was measured on post-deterioration CTs and the lower limit of the 95% confidence interval (95%CI) was the hydrocephalus threshold. In a separate test group (2016), in WFNS ≥ 2 patients, we compared BCI on diagnostic CTs with CSF diversion within 24 hours., Results: The derivation group ( n  = 62) received an external ventricular ( n  = 57, 92%) or lumbar drain ( n  = 5, 8%). Mean post-deterioration BCI was 0.19 (95%CI 0.17-0.22) for age ≤49 years, 0.22 (95%CI 0.20-0.23) for age 50-64 years and 0.24 (95%CI 0.22-0.27) for age ≥65 years. Hydrocephalus thresholds were therefore 0.17, 0.20 and 0.22, respectively. In the test group ( n  = 105), there was no significant difference in BCI on the diagnostic CT between good and poor grade patients aged ≤49 years ( p  = 0.31) and ≥65 years ( p  = 0.96). 30/66 WFNS ≥ 2 patients underwent CSF diversion, although only 15/30 (50%) exceeded BCI thresholds for hydrocephalus., Conclusion: A significant proportion of aSAH patients may undergo CSF diversion without objective evidence of hydrocephalus. Our threshold values require further testing but may provide an objective measure to aid clinical decision making in aSAH.

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.)

Objectives: Right ventricular failure following implantation of a durable left ventricular assist device (LVAD) is a major driver of mortality. Reported survival following biventricular (BiVAD) or total artificial heart (TAH) implantation remains substantially inferior to LVAD alone. We report our outcomes with LVAD and BiVAD HeartMate 3 (HM3)., Methods: Consecutive patients undergoing implantation of an HM3 LVAD between November 2014 and December 2021, at The Alfred, Australia were included in the study. Comparison was made between the BiVAD and LVAD alone groups., Results: A total of 86 patients, 65 patients with LVAD alone and 21 in a BiVAD configuration underwent implantation. The median age of the LVAD and BiVAD groups was 56 years (Interquartile range 46-62) and 49 years (Interquartile range 37-55), respectively. By 4 years after implantation, 54% of LVAD patients and 43% of BiVAD patients had undergone cardiac transplantation. The incidence of stroke in the entire experience was 3.5% and pump thrombosis 5% (all in the RVAD). There were 14 deaths in the LVAD group and 1 in the BiVAD group. The actuarial survival for LVAD patients at 1 year was 85% and BiVAD patients at 1 year was 95%., Conclusions: The application of HM 3 BiVAD support in selected patients appears to offer a satisfactory solution to patients requiring biventricular support., (© 2024 The Authors. Artificial Organs published by International Center for Artificial Organ and Transplantation (ICAOT) and Wiley Periodicals LLC.)

An unprecedented meglumine-based three-component deep eutectic solvent (3c-DES) (MegPAc) was synthesized using meglumine, p-toluenesulfonic acid (PTSA), and acetic acid as a renewable, and non-toxic solvent. The exploitation of the MegPAc as an eco-friendly reaction media to construct a selective and sensitive small organic molecular sensing probe, namely, pyrazolo[5,1-b]quinazoline-3-carboxylates (PQCs) was executed. Captivatingly, the MegPAc served the dual role of solvent and catalyst, and it delivered the title components with 69-94 % yields within 67-150 minutes. Furthermore, a UV-visible study unfolds the selective detection of Cu 2+ ions with our synthetic probe 4 ba and resulted in hypsochromic shift due to electrostatic interactions. Additionally, 1 H NMR titration study and density functional theory (DFT) calculations were performed to attest the binding mechanism of sensing probe 4 ba and Cu 2+ ions. Worthy of mention, this protocol unveils the efficacy of meglumine-based 3c-DES for the first time as a bio-renewable system to synthesize the PQCs., (© 2024 Wiley‐VCH GmbH.)

Herein, we outline a highly efficient PEG-4000-mediated one-pot three-component reaction for the synthesis of 3-imidazolyl indole clubbed 1,2,3-triazole derivatives (5a-r) at up to 96% yield as antiproliferative agents. This three-component protocol offers the advantages of an environmentally benign reaction, excellent yield, quick response time, and operational simplicity triggered by the copper catalyst under microwave irradiation. All the synthesized compounds were tested for antiproliferative activity against six human solid tumor cell lines, that is, A549 and SW1573 (nonsmall cell lung), HBL100 and T-47D (breast), HeLa (cervix), and WiDr (colon). Among them, six compounds, 5g-j, 5m, and 5p, demonstrated effective antiproliferative action with GI 50 values under 10 μM. Furthermore, density functional theory (DFT) calculations were performed for all the synthesized molecules through geometry optimizations, frontier molecular orbital approach, and molecular electrostatic potential (MESP). The theoretical DFT calculation was performed using the DFT/B3LYP/6-31+G (d,p) basis set. Moreover, the biological reactivity of all the representative synthesized molecules was compared with the theoretically calculated quantum chemical descriptors and MESP 3D plots. We also investigated the drug-likeness characteristic and absorption, distribution, metabolism, excretion, and toxicity (ADMET) prediction. In general, our approach enables environmentally friendly access to 3-imidazolyl indole clubbed 1,2,3-triazole derivatives as prospective antiproliferative agents., (© 2023 Deutsche Pharmazeutische Gesellschaft.)

Diversely functionalized pyrazolo-pyridine fused tetrazolo-pyrimidines 10aa-am and 10ba-bn were successfully synthesized via a catalyst-free synthetic protocol with moderate to very good yields. The compounds were evaluated for cytotoxicity against MCF-7 and HEK-293 cells using MTT assay. Among the tested compounds, 10ab (IC 50 - 23.83 µM) and 10ah (IC 50 - 23.30 µM) demonstrated the highest potency against MCF-7 cells, while 10bc (IC 50 - 14.46 µM) and 10bh (IC 50 - 2.53 µM) exhibited excellent cytotoxicity against HEK-293 cells. Additionally, antibacterial screening was performed against three Gram-negative bacteria ( E. coli, P. aeruginosa, and S. enterica ) and three Gram-positive bacteria ( S. aureus, B. megaterium, and B. subtilis ) using broth dilution method, while antifungal activity was assessed against three fungal strains ( A. niger, Penicillium, and S. cerevisiae ) using agar well diffusion method. In antimicrobial screening, the majority of the compounds demonstrated significant antibacterial efficacy compared to antifungal activity. We also conducted comprehensive computational studies, including DFT calculations, molecular docking and dynamics, and drug-likeness assessments. In the DFT study, compounds 10ac and 10bc displayed stable conformations, indicating their potential for higher therapeutic activity. Molecular docking analyses revealed compelling interactions, with compound 10ah demonstrating docking score -7.42 kcal/mol against catalytical domain PARP1 (PDB ID: 7KK4) and 10bh exhibiting a best docking score -10.77 kcal/mol against human corticotropin-releasing factor receptor 1 (PDB ID: 4Z9G). A 100 ns molecular dynamics (MD) simulation study of compounds 10ah and 10bh revealed the stable conformation and binding energy in a stimulating environment. In drug-likeness assessments, both the compounds 10ah and 10bh adhere all the established guidelines.Communicated by Ramaswamy H. Sarma.

Combined retrospective-prospective cohort study was done to know the risk of sensorineural hearing loss in patients of drug resistant Tuberculosis (TB) receiving Anti Tuberculous Treatment (ATT) at tertiary care centre in South Gujarat. Study was done by using retrospective and prospective data of the patients of drug resistant TB of NCHS who received injectable ATT and referred by department of Respiratory Medicine to ENT department for purpose of hearing evaluation pre and post treatment (Case cohort). Age and sex matched control cohort was also used which includes patients of non-drug resistant TB who were not receiving Injectable ATT. Incidence of SNHL in patients taking ATT for drug resistant tuberculosis in our study was 33.9%. The Relative Risk of SNHL was 14.3%. The Attributable Risk of SNHL (preventable SNHL) was 93%., Competing Interests: Conflict of interestThe authors have no financial or non-financial intrest to disclose., (© Association of Otolaryngologists of India 2023. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)

Purpose: Delayed Cerebral Ischaemia (DCI) remains an important preventable driver of poor outcome in aneurysmal subarachnoid haemorrhage (aSAH). Our ability to predict DCI is based on historical patient cohorts, which use inconsistent definitions for DCI. In 2010, a definition of DCI was agreed upon and published by a group of aSAH experts. The aim of this study was to identify predictors using this agreed definition of DCI., Methods: We conducted a literature search of Medline (PubMed) to identify articles published since the publication of the 2010 consensus definition. Risk factors and prediction models for DCI were included if they: (1) adjusted for confounding factors or were derived from randomised trials, (2) were derived from prospectively collected data and (3) included adults with aSAH. The strength of studies was assessed based on quality, risk of bias and applicability of studies using PROBAST., Results: Eight studies totalling 4,542 patients were included from 105 relevant articles from 4,982 records. The most common reason for not including studies was failure to use the consensus definition of DCI (75%). No prediction models were identified in the eligible studies. Significant risk factors for DCI included the presence of onsite neuro-interventional services, high Neuropeptide Y, admission leucocytosis, neutrophil:lymphocyte >5.9 and Fisher Grade > 2. All studies had a high or unclear risk of bias., Conclusions: Only a few studies with high risk of bias have investigated the predictors using consensus-defined DCI. Further studies are warranted to clarify risk factors of DCI in the modern era., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Austria, part of Springer Nature.)

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/ ).)

A straightforward and high yielding synthetic approach is employed to synthesize the novel 1H-1,2,3-triazole tethered pyrazolo[5,1-b]quinazoline hybrids 7(a-t) as new antimicrobial agents with two pharmacophore in the effective two step synthesis. The first step is the four component one-pot synthesis of highly functionalized pyrazolo[5,1-b]quinazolines 5(a-j) catalysed by TBAB, with the advantages of an environmentally benign reaction, high yielding, quick reaction time, and operational simplicity. In the subsequent stage, CuSO 4 /NaAsc system was employed to synthesize the 1H-1,2,3-triazole tethered pyrazolo[1,5-b]quinazoline hybrids as 1H-1,2,3-triazoles are the structures of great diversity and importance in diverse therapeutics containing numerous biological activities. The antimicrobial activity of all the synthesized hybrid compounds have been preliminary tested using the broth dilution technique against two gram-positive and two gram-negative bacterial strains as well as two fungal strains. In comparison to standard drugs, the majority of compounds exhibited good to moderate activity. Among the all the compounds, 7a (MIC 18.54 μM) against Pseudomonas aeruginosa, 7j (MIC 89.76 μM) against Bacillus subtilis as well as Rhizopus oryzae and 7t (MIC 84.88 μM) against Aspergillus parasiticus have remarkable antimicrobial potency as compared to standard drug., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Tricuspid regurgitation is a widely recognised phenomenon in patients with transvenous cardiac rhythm management (CRM) devices. If tricuspid valve repair or replacement is to be considered, what to do with the existing CRM system requires scrutiny with multidisciplinary input. We present a case of multifactorial tricuspid regurgitation in a 48-year-old female with giant cell myocarditis and a transvenous implantable cardioverter-defibrillator (ICD). Key considerations in management and alternative CRM options are discussed., (© 2023 Wiley Periodicals LLC.)

An ultrasound-assisted green protocol for one-pot synthesis of a new series of pharmaceutically relevant pyrazolo quinoline derivatives (4a-t) were synthesized, characterized, and evaluated using DFT and biological activities. Pyrazolo quinoline derivatives (4a-t) were synthesized via a three-component tandem reaction of 1,3-dicarbonyl compound (1a-b), substituted aromatic aldehyde (2a-o), and 5-amino indazole (3a) in the presence of 1-butyl-3-methylimidazolium tetrafluoroborate [BMIM]BF 4 ionic liquid in ethanol at ambient conditions. The main purpose of the present work is selective functionalization of pyrazolo quinoline (4a-t) core excluding another potential parallel reaction under environmentally benign reaction conditions. The present protocol shows features such as amphiphilic behavior of ionic liquid during reaction transformation, and reusability of the [BMIM]BF 4 ionic liquid under mild reaction condition. All newly derived compounds were evaluated for their in vitro anti-inflammatory and antioxidant activity. Among them, compound 4c showed encouraging antioxidant activity compared with standard antioxidant ascorbic acid, and compounds 4n and 4r displayed very good anti-inflammatory activity compared with a standard drug. In this study, a theoretical computational density functional study was also executed to perform the geometry optimizations, frontier molecular orbital approach, and molecular electrostatic potential (MESP). The DFT study was carried out with the basis set DFT/B3LYP/6-31+G (d, p) level of theory. The quantum chemical descriptors (QCDS) and MESP diagrams were plotted to examine the biological reactivities of representative pyrazolo quinolines (4a-t)., (© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Purpose: Due to the risk of intracranial aneurysm (IA) recurrence and the potential requirement for re-treatment following endovascular treatment (EVT), radiological follow-up of these aneurysms is necessary. There is little evidence to guide the duration and frequency of this follow-up. The aim of this study was to establish the current practice in neurosurgical units in the UK and Ireland., Methods: A survey was designed with input from interventional neuroradiologists and neurosurgeons. Neurovascular consultants in each of the 30 neurosurgical units providing a neurovascular service in the UK and Ireland were contacted and asked to respond to questions regarding the follow-up practice for IA treated with EVT in their department., Results: Responses were obtained from 28/30 (94%) of departments. There was evidence of wide variations in the duration and frequency of follow-up, with a minimum follow-up duration for ruptured IA that varied from 18 months in 5/28 (18%) units to 5 years in 11/28 (39%) of units. Young patient age, previous subarachnoid haemorrhage and incomplete IA occlusion were cited as factors that would prompt more intensive surveillance, although larger and broad-necked IA were not followed-up more closely in the majority of departments., Conclusions: There is a wide variation in the radiological follow-up of IA treated with EVT in the UK and Ireland. Further standardisation of this aspect of patient care is likely to be beneficial, but further evidence on the behaviour of IA following EVT is required in order to inform this process., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Austria, part of Springer Nature.)

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

Background: Late referral for heart transplantation (HTx) is associated with worse patient outcomes. There are no universally accepted definitions of what constitutes a timely referral for HTx assessment., Objectives: To evaluate the impact of late referral (LR) on HTx outcomes., Methods: This single-centre retrospective observational study included 80 patients undergoing HTx between 2016-2019. We applied a simple clinical tool, derived from markers of advanced heart failure (HF), to classify LR in HTx patients and assess the impact of LR on HTx outcomes. Outcome measures included duration of intensive care unit (ICU) stay, total hospitalisation stay, cost of transplant admission and one-year mortality., Results: Based upon the clinical profile, LR was defined by the presence of four or more out of 10 criteria for more than 6 months in HTx patients. In this model, 34 patients were timely referrals and 46 were LR. Patients who were LR had: a longer median time between initial diagnosis and referral (3 vs 7 ys; p=0.03); more features of advanced HF, including inotrope requirements (p=0.004); more comorbidities (p=0.014); and hospitalisations (p<0.0001). Late referral was not associated with longer ICU (p=0.14) or hospital stay (p=0.051), however LR incurred greater total in-hospital costs (p=0.011). There was no difference in one-year mortality (6% vs 9%; p=0.64)., Conclusion: Patients referred late for HTx are more unwell at time of referral and require greater in-hospital resource usage at the time of transplantation. Earlier referral for transplant assessment in patients with advanced HF should be encouraged., (Copyright © 2022 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). Published by Elsevier B.V. All rights reserved.)

Abstract: We sought to examine incidence and predictors of eosinophilic myocardial hypersensitivity (EMH) in a cohort of patients in the home inotrope program of a quaternary cardiac transplant center. Patients on home inotropes with progression to heart transplantation or ventricular assist device (VAD) between January 2000 and May 2020 were included. EMH was diagnosed by the presence of an interstitial predominate eosinophilic infiltrate within the myocardium by experienced cardiac pathologists. From a cohort of 74 patients, 58% (43) were on dobutamine and 42% (31) were on milrinone. Dobutamine was associated with EMH incidence of 14% (6/43), with zero cases in the milrinone cohort. Mean age was 52 ± 12 years, 22% were female. More than half (62%) were nonischemic dilated cardiomyopathies, the remainder were ischemic cardiomyopathy. Dobutamine dose [250 (200-282) vs. 225 (200-291) μg/min] and duration of therapy [41 (23-79) vs. 53 (24-91) days] was similar between those with and without EMH. Median change in eosinophil count was 0.31 × 10 9 /L in the EMH group compared with only 0.03 × 10 9 /L in the non-EMH cohort, P = 0.02. Increase in peripheral eosinophil count of >0.20 × 10 9 /L demonstrated good discrimination between those with and without EMH, c-statistic 0.83 (95% CI 0.66-1.0). Heart failure hospitalization occurred in 83% of the EMH group versus 59% in the non-EMH group, P = 0.26. Requirement for VAD was significantly higher in the EMH group (83% vs. 41%, P = 0.05). In conclusion, EMH occurred in 14% of patients receiving home dobutamine. Rising eosinophil count should prompt physicians to consider EMH and switch to milrinone to avoid possible escalation to VAD., Competing Interests: The authors report no conflicts of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

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: The long-term implications of pacemaker insertion in younger adults are poorly described in the literature., Methods: We performed a retrospective analysis of consecutive younger adult patients (18-50 yrs) undergoing pacemaker implantation at a quaternary hospital between 1986-2020. Defibrillators and cardiac resynchronisation therapy devices were excluded. All clinical records, pacemaker checks and echocardiograms were reviewed., Results: Eighty-one (81) patients (median age 41.0 yrs IQR=35-47.0, 53% male) underwent pacemaker implantation. Indications were complete heart block (41%), sinus node dysfunction (33%), high grade AV block (11%) and tachycardia-bradycardia syndrome (7%). During a median 7.9 (IQR=1.1-14.9) years follow-up, nine patients (11%) developed 13 late device-related complications (generator or lead malfunction requiring reoperation [n=11], device infection [n=1] and pocket revision [n=1]). Five (5) of these patients were <40 years old at time of pacemaker insertion. At long-term follow-up, a further nine patients (11%) experienced pacemaker-related morbidity from inadequate lead performance managed with device reprogramming. Sustained ventricular tachycardia was detected in two patients (2%). Deterioration in ventricular function (LVEF decline >10%) was observed in 14 patients (17%) and seven of these patients required subsequent biventricular upgrade. Furthermore, four patients (5%) developed new tricuspid regurgitation (>moderate-severe). Of 69 patients with available long-term pacing data, minimal pacemaker utilisation (pacing <5% at all checks) was observed in 13 (19%) patients., Conclusions: Pacemaker insertion in younger adults has significant long-term implications. Clinicians should carefully consider pacemaker insertion in this cohort given risk of device-related complications, potential for device under-utilisation and issues related to lead longevity. In addition, patients require close follow-up for development of structural abnormalities and arrhythmias., (Copyright © 2022 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). Published by Elsevier B.V. All rights reserved.)

Background: Implantable loop recorders (ILR) are increasingly utilised in the evaluation of unexplained syncope. However, they are expensive and do not protect against future syncope., Objectives: To compare patients requiring permanent pacemaker (PPM) implantation during ILR follow-up with those without abnormalities detected on ILR in order to identify potential predictors of benefit from upfront pacing., Methods: We analysed 100 consecutive patients receiving ILR: Group 1 (n=50) underwent PPM insertion due to bradyarrhythmias detected on ILR; Group 2 (n=50) had no arrhythmias detected on ILR over >3 years follow-up. Baseline clinical characteristics, syncope history, electrocardiographic and echocardiographic parameters were assessed to identify predictors of ultimate requirement for pacing., Results: Group 1 (64% male, median age 70.8 years; IQR 65.5-78.8) were older than Group 2 (58% male, median 60.2 years; IQR 44.0-73.0 p=0.001) and were less likely to have related historical factors such as overheating, posture and exercise (98% vs 70% p<0.001). PR interval was also longer in Group 1 (192±51 vs 169±23 p=0.006) with greater prevalence of distal conduction system disease (30% vs 4.3% p=0.002). Significant univariate predictors for PPM insertion were distal conduction disease (p=0.007), first degree atrioventricular (AV) block (p=0.003), absence of precipitating factors (p=0.004), and age >65 years (p=0.001). Injury sustained, recurrent syncope, history of atrial fibrillation (AF) or heart failure, left atrial (LA) size and left ventricular ejection fraction (LVEF) were not predictive. These significant predictors were incorporated into the DROP score 1 (0-4). Using time-to-event analysis, no patients with a score of 0 progressed to pacing, while higher scores (3-4) strongly predicted pacing requirement (log-rank p<0.001)., Conclusion: The DROP score may be helpful in identifying patients likely to benefit from upfront permanent pacemaker (PPM) insertion following unexplained syncope. Larger prospective studies are required to validate this tool., (Copyright © 2022 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). Published by Elsevier B.V. All rights reserved.)

Background: Since the turn of the century, the prevalence of diabetes mellitus in Australia has increased, primarily due to rising rates of Type 2 diabetes. Simultaneously, the landscape of diabetes medications has evolved significantly. The change in prescribing trends and public spending on diabetes medications within Australia during this period are not well defined., Aims: To establish the frequency and cost of dispensed diabetes medications in the Australian public healthcare system between 2003 and 2019., Methods: We performed a longitudinal nationwide observational study using data obtained from the Pharmaceutical Benefits Scheme (PBS) and Medicare Benefits Schedule websites, which contain information on frequency and spending of diabetes medications dispensed in Australia., Results: The total number of PBS-subsidised prescriptions dispensed for diabetes increased from 5 218 690 in 2003 to 12 188 568 in 2019, and spending increased from $117 241 031 to $598 904 983. Of the non-insulin agents, metformin was consistently the most frequently dispensed agent, with a rapid growth in metformin combination tablets. Dispensation of sulphonylureas and thiazolidinediones have declined, with a simultaneous increase in dipeptidyl peptidase-4 inhibitors, sodium-glucose co-transporter 2 inhibitors and glucagon-like peptide-1 receptor agonists., Conclusions: Our data show a large growth in the use of diabetes medications between 2003 and 2019. The rapid growth in dispensing of drugs with proven cardiovascular and renal benefits reflect the evolving approach of diabetes treatment, from a historical approach targeting glycaemic control alone, to a modern individualised approach targeting specific co-morbidities., (© 2020 Royal Australasian College of Physicians.)

Abstract: To describe the use of levosimendan in a quaternary referral center with a dedicated heart failure service and compare its efficacy and safety to continuous outpatient support with inotropes (COSI) among patients with advanced heart failure (AHF) who require bridge-to-decision (BTD) or bridge-to-transplant (BTT) therapy. This study was a retrospective, single-center, descriptive study of patients with AHF who received either a single levosimendan infusion or COSI between 2018 and 2021. A total of 23 patients received a levosimendan infusion, and 14 were started on COSI. Three indications for levosimendan were identified: (1) to facilitate weaning of continuous inotropes, (2) to augment diuresis in cardiorenal syndrome, and (3) as first-line therapy for cardiogenic shock in selected patients. Eighty-three percent (19 of 23) of patients who received levosimendan survived to discharge, and there were few clinically significant adverse events. Overall survival at 12 months among patients who received levosimendan was 74%. No statistically significant difference in survival was observed at 12 months (P = 0.68) or beyond (P = 0.63) between patients who received levosimendan and were discharged with a plan for BTD or BTT and those who received COSI. Levosimendan is a safe and effective short-term therapy in AHF and offers comparable long-term survival to COSI in patients who require BTD or BTT therapy., Competing Interests: The authors report no conflicts of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

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.)

Background: Patients undergoing heart transplant are at high risk for postoperative vasoplegia. Despite its frequency and association with poor clinical outcomes, there remains no consensus definition for vasoplegia, and the predisposing risk factors for vasoplegia remain unclear. Accordingly, the aim of this study was to evaluate the prevalence, predictors, and clinical outcomes associated with vasoplegia in a contemporary cohort of patients undergoing heart transplantation., Methods: This was a retrospective cohort study of patients undergoing heart transplantation from January 2015 to December 2019. A binary definition of vasoplegia of a cardiac index of 2.5 L/min/m 2 or greater and requirement for norepinephrine (≥5 µg/min), epinephrine (≥4 µg/min), or vasopressin (≥1 unit/h) to maintain a mean arterial blood pressure of 65 mm Hg, for 6 consecutive hours during the first 48 hours postoperatively, was used in determining prevalence. Given the relatively low threshold for the binary definition of vasoplegia, patients were divided into tertiles based on their cumulative vasopressor requirement in the 48 hours following transplant. Outcomes included all-cause mortality, intubation time, intensive care unit length of stay, and length of total hospitalization., Results: After exclusion of patients with primary cardiogenic shock, major bleeding, or overt sepsis, data were collected on 95 eligible patients. By binary definition, vasoplegia incidence was 66.3%. We separately stratified by actual vasopressor requirement tertile (high, intermediate, low). Stratified by tertile, patients with vasoplegia were older (52.7 ± 10.2 vs 46.8 ± 12.7 vs 44.4 ± 11.3 years, P = .02), with higher rates of chronic kidney disease (18.8% vs 32.3% vs 3.1%, P = .01) and were more likely to have been transplanted from left ventricular assist device support (n = 42) (62.5% vs 32.3% vs 37.5%, P = .03). Cardiopulmonary bypass time was prolonged in those that developed vasoplegia (155 min [interquartile range 135-193] vs 131 min [interquartile range 117-152] vs 116 min [interquartile range 102-155], P = .003). Intubation time and length of intensive care unit and hospital stay were significantly increased in those that developed vasoplegia; however, this difference did not translate to a significant increase in all-cause mortality at 30 days or 1 year., Conclusions: Vasoplegia occurs at a high rate after heart transplantation. Older age, chronic kidney disease, mechanical circulatory support, and prolonged bypass time are all associated with vasoplegia; however, this study did not demonstrate an associated increase in all-cause mortality LAY SUMMARY: Patients undergoing heart transplantation are at high risk of vasoplegia, a condition defined by low blood pressure despite normal heart function. We found that vasoplegia was common after heart transplant, occurring in 60%-70% of patients after heart transplant after excluding those with other causes for low blood pressure. Factors implicated included age, poor kidney function, prolonged cardiopulmonary bypass time and preoperative left ventricular assist device support. We found no increased risk of death in patients with vasoplegia despite longer lengths of stay in intensive care and in hospital., Competing Interests: Conflicts of Interest No conflicts of interest., (Crown Copyright © 2021. Published by Elsevier Inc. All rights reserved.)

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.)

The incidence of external ventricular drain (EVD) infections remains high. Chlorhexidine dressings have demonstrated efficacy in reducing infections associated with indwelling catheters at other body sites, although evidence for their use with EVDs is limited. The aim of this systematic review and meta-analysis was to evaluate the efficacy of chlorhexidine dressings in reducing EVD-associated cerebrospinal fluid infection (EVDAI). MEDLINE, EMBASE and the Cochrane library were queried for articles from inception. The primary outcome was the incidence of EVDAI. Secondary outcomes included device safety, microbiological outcomes and shunt-dependency. From 896 unique records, five studies were included of which four presented suitable data for quantitative analysis including three case series and one underpowered randomized controlled trial. There was a high risk of bias in all studies. A total of 880 patients were included with a mean age of 57.7 years (95% confidence interval (CI) 57.4-58.0 years). In primary outcome analysis, the chlorhexidine dressing group had a significantly lower incidence of EVDAI (1.7% vs 7.9%, risk difference (RD) = 0.07, 95% CI 0.00-0.13, P=0.04). In conclusion, chlorhexidine dressings may reduce the incidence of EVDAI but require future study in randomized trials to definitively determine efficacy., (Copyright © 2021 The Healthcare Infection Society. All rights reserved.)

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: Despite advances in the acute care of subarachnoid haemorrhage, longer-term services remain under-developed. Clinical measures are commonly used to assess outcome and quality of life, but patient-reported needs and the extent to which they are met have not been measured. This information is essential to plan and develop evidence-based, patient-centred services. The aim of this study was to describe the frequency and type of self-reported met and unmet needs of subarachnoid haemorrhage survivors, explore whether these differ early and late in recovery and the factors associated with whether needs were met. Methods: A census cross-sectional postal survey of 400 subarachnoid haemorrhage survivors discharged from a large neurosurgical unit. The Self-Reported Needs after Stroke Questionnaire was modified and used to measure the self-reported needs of subarachnoid haemorrhage survivors and the extent to which they were met 1-2 years and 3-5 years post haemorrhage. Results: 203 (51%) participants responded: 122/260 (47%) from the early and 81/143 (57%) from the late cohort. 63% were female; mean age was 55 years. 86% of survivors reported one or more need, and 78% reported at least one unmet need (median 6, range 1-19). The most commonly reported need related to fatigue (66%). This and several other health needs were reported as unmet in over 80% of identified cases. We found no consistent factors that were associated with needs remaining unmet. Conclusion: Most subarachnoid haemorrhage survivors in both cohorts had unmet needs. Future research should aim to inform the development of post-discharge services to address the persistent long-term needs identified.Implications for rehabilitationSubarachnoid haemorrhage survivors report a number of needs 1-2 years and 3-5 years post haemorrhage.Needs relating to fatigue, memory, concentration, headache and anxiety were the most commonly reported.A large proportion of needs were described as unmet.The design of rehabilitation services for subarachnoid haemorrhage survivors should consider the self-reported needs described in this study.