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Background & aims\nCardiovascular disease (CVD) impacts significantly health and social care systems as well as society through premature mortality and disability, with patients requiring care from relatives. Previous pan-European estimates of the economic burden of CVD are now outdated. This study aims to provide novel, up-to-date evidence on the economic burden across the 27 European Union (EU) countries in 2021. \n\nMethods\nAggregate country-specific resource use data on morbidity, mortality, and health, social and informal care were obtained from international sources, such as the Statistical Office of the European Communities, enhanced by data from the European Society of Cardiology Atlas programme and patient-level data from the Survey of Health, Ageing and Retirement in Europe. Country-specific unit costs were used, with cost estimates reported on a per capita basis, after adjustment for price differentials. \n \nResults\nCVD is estimated to cost the EU \u20ac282 billion annually, with health and long-term care accounting for \u20ac155 billion (55%), equalling 11% of EU-health expenditure. Productivity losses accounted for 17% (\u20ac48 billion), whereas informal care costs were \u20ac79 billion (28%). CVD represented a cost of \u20ac630 per person, ranging from \u20ac381 in Cyprus to \u20ac903 in Germany. Coronary heart disease accounted for 27% (\u20ac77 billion) and cerebrovascular diseases for 27% (\u20ac76 billion) of CVD costs. \n\nConclusions\nThis study provides contemporary estimates of the wide-ranging impact of CVD on all aspects of the economy. The data help inform evidence based polices to reduce the impact of CVD, promoting care access and better health outcomes and economic sustainability.
\n \n\n \n \nHistorically, the NHS did not routinely collect cost data, unlike many countries with private insurance markets. In 1998, for the first time the government mandated NHS trusts to submit estimates of their costs of service, known as reference costs. These have informed a wide range of health economic evaluations and important functions in the health service, such as setting prices.Reference costs are collected by progressively disaggregating budgets top-down into disease and treatment groups. Despite ongoing improvements to methods and guidance, these submissions continued to suffer a lack of accuracy and comparability, fundamentally undermining their credibility for critical functions.To overcome these issues, there was a long-held ambition to collect \"patient-level\" cost data. Patient-level costs are estimated with a combination of disaggregating budgets but also capturing the patient-level \"causality of costs\" bottom-up in the allocation of resources to patient episodes. These not only aim to capture more of the drivers of costs, but also improve consistency of reporting between providers.The change in methods may confer improvements to data quality, though judgement is still required and achieving consistency between trusts will take further work. Estimated costs may also change in important ways that may take many years to fully understand. We end on a cautionary note that patient-level cost methods may unlock potential, they alone contribute little to our understanding of the complexities involved with service quality or need, while that potential will require substantial investment to realise. Many healthcare resources cannot be attributed to individual patients so the very notion of \"patient-level\" costs may be misplaced. High hopes have been put in these new data, though much more work is now necessary to understand their quality, what they show and how their use will impact the system.
\n \n\n \n \nUp to 80% of Parkinson's disease patients develop dementia, but time to dementia varies widely from motor symptom onset. Dementia with Lewy bodies presents with clinical features similar to Parkinson's disease dementia, but cognitive impairment precedes or coincides with motor onset. It remains controversial whether dementia with Lewy bodies and Parkinson's disease dementia are distinct conditions or represent part of a disease spectrum. The biological mechanisms underlying disease heterogeneity, in particular the development of dementia, remain poorly understood, but will likely be key to understanding disease pathways and ultimately therapy development. Previous genome-wide association studies in Parkinson's disease and dementia with Lewy bodies/Parkinson's disease dementia have identified risk loci differentiating patients from controls. We collated data for 7,804 patients of European ancestry from Tracking Parkinson's (PRoBaND), The Oxford Discovery Cohort, and AMP-PD. We conducted a discrete phenotype genome-wide association studies comparing Lewy body diseases with and without dementia to decode disease heterogeneity by investigating the genetic drivers of dementia in Lewy body diseases. We found that risk alleles rs429358 tagging APOEe4 and rs7668531 near the MMRN1 and SNCA-AS1 genes, increase the odds of developing dementia and that an intronic variant rs17442721 tagging LRRK2 G2019S, on chromosome 12 is protective against dementia. These results should be validated in autopsy confirmed cases in future studies.
\n \n\n \n \nFreezing-of-gait (FOG) and impaired walking are common features of Parkinson's disease (PD). Provision of external stimuli (cueing) can improve gait, however, many cueing methods are simplistic, increase task loading or have limited utility in a real-world setting. Closed-loop (automated) somatosensory cueing systems have the potential to deliver personalised, discrete cues at the appropriate time, without requiring user input. Further development of cue delivery methods and FOG-detection are required to achieve this. In this feasibility study, we aimed to test if FOG-initiated vibration cues applied to the lower-leg via wearable devices can improve gait in PD, and to develop real-time FOG-detection algorithms. 17 participants with Parkinson's disease and daily FOG were recruited. During 1\u00a0h study sessions, participants undertook 4 complex walking circuits, each with a different intervention: continuous rhythmic vibration cueing (CC), responsive cueing (RC; cues initiated by the research team in response to FOG), device worn with no cueing (NC), or no device (ND). Study sessions were grouped into 3 stages/blocks (A-C), separated by a gap of several weeks, enabling improvements to circuit design and the cueing device to be implemented. Video and onboard inertial measurement unit (IMU) data were analyzed for FOG events and gait metrics. RC significantly improved circuit completion times demonstrating improved overall performance across a range of walking activities. Step frequency was significantly enhanced by RC during stages B and C. During stage C,\u2009>\u200910 FOG events were recorded in 45% of participants without cueing (NC), which was significantly reduced by RC. A machine learning framework achieved 83% sensitivity and 80% specificity for FOG detection using IMU data. Together, these data support the feasibility of closed-loop cueing approaches coupling real-time FOG detection with responsive somatosensory lower-leg cueing to improve gait in PD.
\n \n\n \n \nMutations in the ubiquitously expressed DNA/RNA binding protein FUS cause aggressive juvenile forms of amyotrophic lateral sclerosis (ALS). While most FUS mutation studies have focused on motor neuron degeneration, little is known about wider systemic or developmental effects. We studied pleiotropic phenotypes in a physiological knock-in mouse model carrying the pathogenic FUSDelta14 mutation in homozygosity. RNA sequencing of multiple organs aimed to identify pathways altered by the mutant protein in the systemic transcriptome, including metabolic tissues given the link between ALS-FTD and altered metabolism. Few genes were commonly altered across all tissues, and most genes and pathways affected were generally tissue-specific. Phenotypic assessment of mice revealed systemic metabolic alterations related to the pathway changes identified. MRI brain scans and histological characterisation revealed that homozygous FUSDelta14 brains were smaller and displayed significant morphological alterations including a thinner cortex, reduced neuronal number and increased gliosis, which correlated with early cognitive impairment and fatal seizures. We show that the disease aetiology of FUS mutations can include both neurodevelopmental and systemic alterations.
\n \n\n \n \nNo one doubts the significant variation in the practice of transfusion medicine. Common examples are the variability in transfusion thresholds and the use of tranexamic acid for surgery with likely high blood loss despite evidence-based standards. There is a long history of applying different strategies to address this variation, including education, clinical guidelines, audit and feedback, but the effectiveness and cost-effectiveness of these initiatives remains unclear. Advances in computerised decision support systems and the application of novel electronic capabilities offer alternative approaches to improving transfusion practice. In England, the National Institute for Health and Care Research funded a Blood and Transplant Research Unit (BTRU) programme focussing on 'A data-enabled programme of research to improve transfusion practices'. The overarching aim of the BTRU is to accelerate the development of data-driven methods to optimise the use of blood and transfusion alternatives, and to integrate them within routine practice to improve patient outcomes. One particular area of focus is implementation science to address variation in practice.
\n \n\n \n \nAbstractBackgroundPeripheral nerve biopsy is a valuable final diagnostic tool; however, histopathological results can be non\u2010diagnostic.AimsWe aim to identify quality improvement measures by evaluating the pre\u2010biopsy assessment and diagnostic yield of specific histopathological diagnosis.MethodsThis was a retrospective study based on 10\u2009years of experience with peripheral nerve biopsies at a single centre. Clinical data were obtained regarding pre\u2010biopsy history, examination, serum and cerebrospinal fluid (CSF) investigations, neurophysiology and peripheral nerve imaging. Based upon a histopathological outcome, patients were grouped into vasculitis, granulomatous and infiltrative (diagnostic) group, or a comparison group of non\u2010specific axonal neuropathy and normal (non\u2010specific/normal) group.ResultsFrom a cohort of 64 patients, 21 (32.8%) were included in the diagnostic group and 30 (46.9%) in the non\u2010specific/normal group. Clinical parameters associated with the diagnostic group were shorter history (mean 10.2 months vs 38.1), stepwise progression (81% vs 20%), neuropathic pain (85.7% vs 56.7%), vasculitic rash (23.8% vs 0%), mononeuritis multiplex (57.1% vs 10%), asymmetry (90.5% vs 60%), raised white cell count (47.6% vs 16.7%), myeloperoxidase antibody (19.1% vs 0%) and abnormal peripheral nerve imaging (33.3% vs 10%).ConclusionSelection of patients undergoing nerve biopsy requires careful consideration of clinical parameters, including peripheral nerve imaging. Several quality improvement measures are proposed to improve yield of clinically actionable information from nerve biopsy.
\n \n\n \n \nAbstract\nValid, responsive blood biomarkers specific to peripheral nerve damage would improve management of peripheral nervous system (PNS) diseases. Neurofilament light chain (NfL) is sensitive for detecting axonal pathology but is not specific to PNS damage, as it is expressed throughout the PNS and CNS. Peripherin, another intermediate filament protein, is almost exclusively expressed in peripheral nerve axons. We postulated that peripherin would be a promising blood biomarker of PNS axonal damage.\nWe demonstrated that peripherin is distributed in sciatic nerve, and to a lesser extent spinal cord tissue lysates, but not in brain or extra-neural tissues. In the spinal cord, anti-peripherin antibody bound only to the primary cells of the periphery (anterior horn cells, motor axons and primary afferent sensory axons). In vitro models of antibody-mediated axonal and demyelinating nerve injury showed marked elevation of peripherin levels only in axonal damage and only a minimal rise in demyelination.\nWe developed an immunoassay using single molecule array technology for the detection of serum peripherin as a biomarker for PNS axonal damage. We examined longitudinal serum peripherin and NfL concentrations in individuals with Guillain-Barr\u00e9 syndrome (GBS, n = 45, 179 time points), chronic inflammatory demyelinating polyradiculoneuropathy (CIDP, n = 35, 70 time points), multiple sclerosis (n = 30), dementia (as non-inflammatory CNS controls, n = 30) and healthy individuals (n = 24).\nPeak peripherin levels were higher in GBS than all other groups (median 18.75\u2005pg/ml versus < 6.98\u2005pg/ml, P < 0.0001). Peak NfL was highest in GBS (median 220.8\u2005pg/ml) and lowest in healthy controls (median 5.6\u2005pg/ml), but NfL did not distinguish between CIDP (17.3\u2005pg/ml), multiple sclerosis (21.5\u2005pg/ml) and dementia (29.9\u2005pg/ml). While peak NfL levels were higher with older age (rho = +0.39, P < 0.0001), peak peripherin levels did not vary with age.\nIn GBS, local regression analysis of serial peripherin in the majority of individuals with three or more time points of data (16/25) displayed a rise-and-fall pattern with the highest value within the first week of initial assessment. Similar analysis of serial NfL concentrations showed a later peak at 16 days. Group analysis of serum peripherin and NfL levels in GBS and CIDP patients were not significantly associated with clinical data, but in some individuals with GBS, peripherin levels appeared to better reflect clinical outcome measure improvement.\nSerum peripherin is a promising new, dynamic and specific biomarker of acute PNS axonal damage.
\n \n\n \n \nCurrently, several vaccines and antivirals across the globe are in clinical trials. Hydroxychloroquine (HCQ) was reported to inhibit the SARS-CoV-2 virus in antiviral assays. Here, it raises the curiosity about the molecular target of HCQ inside the cell. It may inhibit some of the viral targets, or some other complex mechanisms must be at disposal towards action mechanisms. In some of the viruses, proteases are experimentally reported to be a potential target of HCQ. However, no in-depth investigations are available in the literature yet. Henceforth, we have carried out extensive, one-microsecond long molecular dynamics simulations of the bound complex of hydroxychloroquine with main protease (Mpro) of SARS-CoV-2. Our analysis found that HCQ binds within the catalytic pocket of Mpro and remains stable upto one-third of simulation time but further causes increased fluctuations in simulation parameters. In the end, the HCQ does not possess any pre-formed hydrogen bond, other non-covalent interactions with Mpro, ultimately showing the unsteadiness in binding at catalytic binding pocket and may suggest that HCQ may not inhibit the Mpro. In the future, this study would require experimental validation on enzyme assays against Mpro, and that may be the final say. Communicated by Ramaswamy H. Sarma.
\n \n\n \n \nThe intrinsically disordered proteins/regions (IDPs/IDPRs) are known to be responsible for multiple cellular processes and are associated with many chronic diseases. In viruses, the existence of a disordered proteome is also proven and is related to its conformational dynamics inside the host. The SARS-CoV-2 has a large proteome, in which, structure and functions of all proteins are not known yet, along with non-structural protein 11 (nsp11). In this study, we have performed extensive experimentation on nsp11. Our results based on the CD spectroscopy gives characteristic disordered spectrum for IDPs. Further, we investigated the conformational behavior of nsp11 in the presence of membrane mimetic environment, \u03b1-helix inducer, and natural osmolyte. In the presence of negatively charged and neutral liposomes, nsp11 remains disordered. However, with SDS micelle, it adopted an \u03b1-helical conformation, suggesting the helical propensity of nsp11. Finally, we again confirmed the IDP behavior of nsp11 using MD simulations. In future, this conformational dynamic study could help to clarify its functional importance in SARS-CoV-2 infection.
\n \n\n \n \nINTRODUCTION: The ongoing life-threatening pandemic of coronavirus disease 2019 (COVID-19) has extensively affected the world. During this global health crisis, it is fundamentally crucial to find strategies to combat SARS-CoV-2. Despite several efforts in this direction and continuing clinical trials, no vaccine has been approved for it yet. METHODS: To find a preventive measure, we have computationally designed a multi-epitopic subunit vaccine using immuno-informatic approaches. RESULTS: The structural proteins of SARS-CoV-2 involved in its survival and pathogenicity were used to predict antigenic epitopes. The antigenic epitopes were capable of eliciting a strong humoral as well as cell-mediated immune response, our predictions suggest. The final vaccine was constructed by joining the all epitopes with specific linkers and to enhance their stability and immunogenicity. The physicochemical property of the vaccine was assessed. The vaccine 3D structure prediction and validation were done and docked with the human TLR-3 receptor. Furthermore, molecular dynamics simulations of the vaccine-TLR-3 receptor complex are employed to assess its dynamic motions and binding stability in-silico. CONCLUSION: Based on this study, we strongly suggest synthesizing this vaccine, which further can be tested in-vitro and in-vivo to check its potency in a cure for COVID-19.
\n \n\n \n \nJapanese encephalitis virus (JEV) is one of the major causes of viral encephalitis all around the globe. Approximately 3\u00a0billion people in endemic areas are at risk of Japanese encephalitis. To develop a wholistic understanding of the viral proteome, it is important to investigate both its ordered and disordered proteins. However, the functional and structural significance of disordered regions in the JEV proteome has not been systematically investigated as of yet. To fill this gap, we used here a set of bioinformatics tools to analyze the JEV proteome for the predisposition of its proteins for intrinsic disorder and for the presence of the disorder-based binding regions (also known as molecular recognition features, MoRFs). We also analyzed all JEV proteins for the presence of the probable nucleic acid-binding (DNA and RNA) sites. The results of these computational studies are experimentally validated using JEV capsid protein as an illustrative example. In agreement with bioinformatic analysis, we found that the N-terminal region of the JEV capsid (residues 1-30) is intrinsically disordered. We showed that this region is characterized by the temperature response typical for highly disordered proteins. Furthermore, we have experimentally shown that this disordered N-terminal domain of a capsid protein has a noticeable 'gain-of-structure' potential. In addition, using DOPS liposomes, we demonstrated the presence of pronounced membrane-mediated conformational changes in the N-terminal region of JEV capsid. In our view, this disorder-centric analysis would be helpful for a better understanding of the JEV pathogenesis.
\n \n\n \n \nAims: c-Myc, along with its partner MAX, regulates the expression of several genes, leading to an oncogenic phenotype. The MAX interacting interface of c-Myc is disordered and uncharacterized for small molecule binding. Salvianolic acid B possesses numerous therapeutic properties, including anticancer activity. The current study was designed to elucidate the interaction of the Sal_Ac_B with the disordered bHLH domain of c-Myc using computational and biophysical techniques. Materials &\u00a0methods: The binding of Sal_Ac_B with Myc was studied using computational and biophysical techniques, including molecular docking and simulation, fluorescence lifetime, circular dichroism and anisotropy. Results &\u00a0conclusions: The study demonstrated a high binding potential of Sal_Ac_B against the disordered Myc peptide. The binding of the compounds leads to an overall conformational change in Myc. Moreover, an extensive simulation study showed a stable Sal_Ac_B/Myc binding.
\n \n\n \n \nc-Myc is a transcription factor that plays a crucial role in cellular homeostasis, and its deregulation is associated with highly aggressive and chemotherapy-resistant cancers. After binding with partner MAX, the c-Myc-MAX heterodimer regulates the expression of several genes, leading to an oncogenic phenotype. Although considered a crucial therapeutic target, no clinically approved c-Myc-targeted therapy has yet been discovered. Here, we report the discovery via computer-aided drug discovery of a small molecule, L755507, which functions as a c-Myc inhibitor to efficiently restrict the growth of diverse Myc-expressing cells with low micromolar IC50 values. L755507 successfully disrupts the c-Myc-MAX heterodimer, resulting in decreased expression of c-Myc target genes. Spectroscopic and computational experiments demonstrated that L755507 binds to the c-Myc peptide and thereby stabilizes the helix-loop-helix conformation of the c-Myc transcription factor. Taken together, this study suggests that L755507 effectively inhibits the c-Myc-MAX heterodimerization and may be used for further optimization to develop a c-Myc-targeted antineoplastic drug.
\n \n\n \n \nGiven the COVID-19 pandemic, currently, there are many drugs in clinical trials against this virus. Among the excellent drug targets of SARS-CoV-2 are its proteases (Nsp3 and Nsp5) that plays vital role in polyprotein processing giving rise to functional nonstructural proteins, essential for viral replication and survival. Nsp5 (also known as Mpro) hydrolyzes replicase polyprotein (1ab) at eleven different sites. For targeting Mpro, we have employed drug repurposing approach to identify potential inhibitors of SARS-CoV-2 in a shorter time span. Screening of approved drugs through docking reveals Hyaluronic acid and Acarbose among the top hits which are showing strong interactions with catalytic site residues of Mpro. We have also performed docking of drugs Lopinavir, Ribavirin, and Azithromycin on SARS-CoV-2 Mpro. Further, binding of these compounds (Hyaluronic acid, Acarbose, and Lopinavir) is validated by extensive molecular dynamics simulation of 500\u2009ns where these drugs show stable binding with Mpro. We believe that the high-affinity binding of these compounds will help in designing novel strategies for structure-based drug discovery against SARS-CoV-2.Communicated by Ramaswamy H. Sarma.
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