Estimating demand for potential disease-modifying therapies for Alzheimer's disease in the UK.

BACKGROUND: Phase three trials of the monoclonal antibodies lecanemab and donanemab, which target brain amyloid, have reported statistically significant differences in clinical end-points in early Alzheimer's disease. These drugs are already in use in some countries and are going through the regulatory approval process for use in the UK. Concerns have been raised about the ability of healthcare systems, including those in the UK, to deliver these treatments, considering the resources required for their administration and monitoring. AIMS: To estimate the scale of real-world demand for monoclonal antibodies for Alzheimer's disease in the UK. METHOD: We used anonymised patient record databases from two National Health Service trusts for the year 2019 to collect clinical, demographic, cognitive and neuroimaging data for these cohorts. Eligibility for treatment was assessed using the inclusion criteria from the clinical trials of donanemab and lecanemab, with consideration given to diagnosis, cognitive performance, cerebrovascular disease and willingness to receive treatment. RESULTS: We examined the records of 82 386 people referred to services covering around 2.2 million people. After applying the trial criteria, we estimate that a maximum of 906 people per year would start treatment with monoclonal antibodies in the two services, equating to 30 200 people if extrapolated nationally. CONCLUSIONS: Monoclonal antibody treatments for Alzheimer's disease are likely to present a significant challenge for healthcare services to deliver in terms of the neuroimaging and treatment delivery. The data provided here allows health services to understand the potential demand and plan accordingly.

Formulation of Ensulizole with Beta-Cyclodextrins for Improved Sunscreen Activity and Biocompatibility.

In today's context, prolonged exposure to sunlight is widely recognized as a threat to human health, leading to a range of adverse consequences, including skin cancers, premature skin aging, and erythema. To mitigate these risks, preventive actions mainly focus on advocating the application of sunscreen lotions and minimizing direct exposure to sunlight. This research study specifically centered on ensulizole (ENS), a prominent ingredient in sunscreens. The objective was to create inclusion complexes (ICs) with Beta-cyclodextrin (B-CD) and its hydroxypropyl derivatives (H-CD). Using phase solubility measurements, we determined that both B-CD and H-CD form 1:1 stoichiometric ICs with ENS. Proton nuclear magnetic resonance spectral (1H NMR) analysis confirmed that the phenyl portion of ENS is encapsulated within the B-CD cavity. Significant changes in surface morphology were observed during the formation of these ICs compared to ENS and CDs alone. Quantum mechanical calculations were employed to further support the formation of ICs by providing energy data. Particularly, the photostability of the ENS:B-CD ICs remained intact for up to four hours of UV exposure, with no significant alterations in the structure of ENS. Furthermore, comprehensive biocompatibility assessments yielded encouraging results, suggesting the potential application of these inclusion complexes in cosmetics as a UVB sunscreen. In summary, our research underscores the successful creation of inclusion complexes characterized by enhanced photostability and safe biocompatibility.

Adenosine/ß-Cyclodextrin-Based Metal-Organic Frameworks as a Potential Material for Cancer Therapy.

Recently, researchers have employed metal-organic frameworks (MOFs) for loading pharmaceutically important substances. MOFs are a novel class of porous class of materials formed by the self-assembly of organic ligands and metal ions, creating a network structure. The current investigation effectively achieves the loading of adenosine (ADN) into a metal-organic framework based on cyclodextrin (CD) using a solvent diffusion method. The composite material, referred to as ADN:ß-CD-K MOFs, is created by loading ADN into beta-cyclodextrin (ß-CD) with the addition of K+ salts. This study delves into the detailed examination of the interaction between ADN and ß-CD in the form of MOFs. The focus is primarily on investigating the hydrogen bonding interaction and energy parameters through the aid of semi-empirical quantum mechanical computations. The analysis of peaks that are associated with the ADN-loaded ICs (inclusion complexes) within the MOFs indicates that ADN becomes incorporated into a partially amorphous state. Observations from SEM images reveal well-defined crystalline structures within the MOFs. Interestingly, when ADN is absent from the MOFs, smaller and irregularly shaped crystals are formed. This could potentially be attributed to the MOF manufacturing process. Furthermore, this study explores the additional cross-linking of ß-CD with K through the coupling of -OH on the ß-CD-K MOFs. The findings corroborate the results obtained from FT-IR analysis, suggesting that ß-CD plays a crucial role as a seed in the creation of ß-CD-K MOFs. Furthermore, the cytotoxicity of the MOFs is assessed in vitro using MDA-MB-231 cells (human breast cancer cells).

Supramolecular ß-Cyclodextrin-Quercetin Based Metal-Organic Frameworks as an Efficient Antibiofilm and Antifungal Agent.

The loading of drugs or medicinally active compounds has recently been performed using metal-organic frameworks (MOFs), which are thought to be a new type of porous material in which organic ligands and metal ions can self-assemble to form a network structure. The quercetin (QRC) loading and biofilm application on a cyclodextrin-based metal-organic framework via a solvent diffusion approach is successfully accomplished in the current study. The antibacterial plant flavonoid QRC is loaded onto ß-CD-K MOFs to create the composite containing inclusion complexes (ICs) and denoted as QRC:ß-CD-K MOFs. The shifting in the chemical shift values of QRC in the MOFs may be the reason for the interaction of QRC with the ß-CD-K MOFs. The binding energies and relative contents of MOFs are considerably changed after the formation of QRC:ß-CD-K MOFs, suggesting that the interactions took place during the loading of QRC. Confocal laser scanning microscopy (CLSM) showed a reduction in the formation of biofilm. The results of the cell aggregation and hyphal growth are consistent with the antibiofilm activity that is found in the treatment group. Therefore, QRC:ß-CD-K MOFs had no effect on the growth of planktonic cells while inhibiting the development of hyphae and biofilm in C. albicans DAY185. This study creates new opportunities for supramolecular ß-CD-based MOF development for use in biological research and pharmaceutical production.

What training should psychiatrists have to interpret six- and 12-lead electrocardiograms?

To monitor for drug-related cardiac arrhythmias, psychiatrists regularly perform and interpret 12-lead (12L) and, increasingly often, six-lead (6L) electrocardiograms (ECGs). It is not known how training on this complex skill is updated or how well psychiatrists can interpret relevant arrhythmias on either device.We conducted an online survey and ECG interpretation test of cardiac rhythms relevant to psychiatrists.A total of 183 prescribers took part; 75% did not regularly update their ECG interpretation skills, and only 22% felt confident in interpreting ECGs. Most participants were able to recognise normal ECGs. For both 6L and 12L ECGs, the majority of participants were able to recognise abnormal ECGs, but fewer than 50% were able to correctly identify relevant arrhythmias (complete heart block and long QTc). A small number prescribed in the presence of potentially fatal arrhythmias. These findings suggest a need for mandatory ECG interpretation training to improve safe prescribing practice.

Host-guest interaction studies of polycyclic aromatic hydrocarbons (PAHs) in alkoxy bridged binuclear rhenium (I) complexes.

The interaction of two neutral alkoxy bridged binuclear rhenium(I) complexes, 1 and 2 [{Re(CO)3(1,4-NVP)}2(µ2-OR)2] (1, R = C4H9; 2, R = C10H21; 1,4-NVP = 4-(1-naphthylvinyl)pyridine] with polycyclic aromatic hydrocarbons (PAH) is investigated. UV-vis absorption, emission, 1H NMR spectral titrations, TCSPC lifetime studies and DFT theoretical calculations were carried out to examine the binding responses of complexes 1 and 2 with various PAHs such as pyrene, naphthalene, anthracene and phenanthrene. The UV-Vis absorption spectra showed an increase in absorbance of the metal-to ligand charge-transfer (MLCT) and ligand centered (LC) bands upon addition of various PAH molecules to 1 and 2, whereas the emission behavior was found to show emission quenching, which might occur through energy transfer pathway. The binding constants (K) of complexes 1 and 2 for various PAHs are found to be in the order of 104 M-1 with a 1:1 binding mode, as determined from UV-vis absorption and emission spectral titration studies. 1H NMR spectral studies show that the chemical shifts of pyrene guest and the 1,4-NVP moiety of 2 are shifted up-field, whilst the alkoxy protons do not show any appreciable change in their chemical shifts. It is believed that the open cavities present in the Re(I) complexes may lead to the recognition of PAHs via CH···π interaction.

Can healthy lifestyle modify risk factors for dementia? Findings from a pilot community-based survey in Chennai (India) and Newcastle (UK).

BACKGROUND: Currently there are no effective treatments available for dementia. Attention has turned to defining preventive strategies and identifying modifying effects of lifestyle, including physical activity, diet, alcohol intake and smoking, in reducing cognitive decline and overt memory problems in the elderly. METHODS: In this study, we addressed the modifying aspects of various components of lifestyle in two ageing samples and explored the possible effects that exercise, diet and spiritual and religious beliefs have upon physical and mental health. A total of 251 subjects (128 in Chennai, India, and 123 in Newcastle, UK) filled in a questionnaire regarding their lifestyle habits. Data were analysed with χ² analysis. RESULTS: Our findings highlight that spiritual and religious beliefs promoted good physical and mental health and were negatively associated with risk factors for dementia, such as high blood pressure, high cholesterol level and diabetes. Lifelong diet and physical activity also contributed to better overall well-being in both samples. CONCLUSIONS: Our study suggests substantial lifestyle variations between two urban populations in Chennai, India, and Newcastle-upon-Tyne, UK. Further detailed work is required to identify the lifestyle components that have the greatest impact on modifying the known risk factors for dementia.

A consensus rating method for small virus-retentive filters. I. Method development.

Virus filters are membrane-based devices that remove large viruses (e.g., retroviruses) and/or small viruses (e.g., parvoviruses) from products by a size exclusion mechanism. In 2002, the Parenteral Drug Association (PDA) organized the PDA Virus Filter Task Force to develop a common nomenclature and a standardized test method for classifying and identifying viral-retentive filters. One goal of the task force was to develop a test method for small virus-retentive filters. Because small virus-retentive filters present unique technical challenges, the test method development process was guided by laboratory studies to determine critical variables such as choice of bacteriophage challenge, choice of model protein, filtration operating parameters, target log10 reduction value, and filtration endpoint definition. Based on filtration, DLS, electrospray differential mobility analysis, and polymerase chain reaction studies, a final rating based on retention of bacteriophage PP7 was chosen by the PDA Virus Filter Task Force. The detailed final consensus filter method was published in the 2008 update of PDA Technical Report 41. Virus Filtration.

A consensus rating method for small virus-retentive filters. II. Method evaluation.

Virus filters are membrane-based devices that remove large viruses (e.g., retroviruses) and/or small viruses (e.g., parvoviruses) from products by a size exclusion mechanism. In 2002, the Parenteral Drug Association (PDA) organized the PDA Virus Filter Task Force to develop a common nomenclature and a standardized test method for classifying and identifying viral-retentive filters. A test method based on bacteriophage PP7 retention was chosen based on developmental studies. The detailed final consensus filter method is published in the 2008 update of PDA Technical Report 41: Virus Filtration. Here, we evaluate the method and find it to be acceptable for testing scaled-down models of small virus-retentive filters from four manufacturers. Three consecutive lots of five filter types were tested (Pegasus SV4, Viresolve NFP, Planova 20N and 15N, Virosart CPV). Each passed the criteria specified in the test method (i.e., >4 log10 PP7 retention, >90% intravenous immunoglobulin passage, and passing integrity/installation testing) and was classified as PP7-LRV4.

Diffusion tensor imaging in dementia with Lewy bodies and Alzheimer's disease.

Dementia with Lewy bodies (DLB) is a common form of dementia, with fewer memory deficits, and more visuo-perceptual problems than Alzheimer's disease (AD). We hypothesized that there would be disease specific alterations revealed by diffusion tensor imaging with AD showing temporal lobe and DLB more parietal changes. We recruited 15 people with AD, 16 with DLB, and 15 healthy control subjects of similar age. They were scanned on a 1.5 T MRI system with diffusion tensor FLAIR imaging. Apparent diffusion coefficient (ADC) and fractional anisotropy (FA) maps were calculated, and data were analysed using pre-defined regions of interest (ROI) and also with SPM. We found a significant decrease in the FA map in a ROI in the parietal lobe (precuneus) of the DLB group. Using SPM we found increased ADC in the left temporal lobe of AD subjects compared to controls. There were no other significant differences between groups. We conclude that there are subtle changes visible with diffusion imaging in DLB and AD which may reflect disrupted connectivity and underlie observed perfusion changes in these disorders.

Atrophy is associated with posterior cingulate white matter disruption in dementia with Lewy bodies and Alzheimer's disease.

Hippocampal atrophy and posterior cingulate hypometabolism are common features of both Alzheimer's disease (AD) and dementia with Lewy bodies (DLB). These regions show correlated activity at rest as part of the 'default network', and they are connected by the cingulum, a white matter (WM) tract. We hypothesised that hippocampal atrophy would be associated with disruption of the cingulum, as determined by diffusion tensor imaging. We recruited 15 people with AD, 16 with DLB, and 15 healthy control subjects of similar age. They were scanned on a 1.5 T MRI system with a T1 weighted 3D sequence and diffusion tensor FLAIR imaging. The T1 images were segmented into grey and white matter and spatially normalised using SPM. Hippocampal atrophy was estimated by calculating the mean grey matter (GM) volume from a region of interest in standard space and global atrophy from the total CSF segmentation. Fractional anisotropy (FA) maps were calculated and also spatially normalised. Using SPM, a multivariate correlation of FA against hippocampal GM, global atrophy and disease group was performed. We found a bilateral region adjacent to the posterior cingulate and encompassing a branch of the cingulum where global atrophy correlated with fractional anisotropy, after controlling for diagnosis and hippocampal GM. The results suggest that dementia disease progression as measured by global atrophy is associated with disruption of the white matter which connects posterior cingulate and lateral parietal regions. Hence, in addition to the hypometabolism in these regions in AD and DLB, there is also disruption to the white matter connecting them. Future studies are needed to determine whether the disruption precedes or is consequent on atrophy or hypometabolism.

Relationship between periventricular and deep white matter lesions and depressive symptoms in older people. The LADIS Study.

BACKGROUND: Both types of cerebral white matter hyperintensities, periventricular (PVL) and deep white matter lesions (DWML) have been previously associated with the development of depression in older subjects. However, it remains controversial as to whether PVL, DWML, or both are most strongly associated with depression and this was the aim of the current study. METHODS: In a pan-European multicentre study of 626 older subjects, we examined the relationship between PVL and DWML, depressive symptoms (GDS quintile), cognitive status (MMSE), hypertension and history of stroke. RESULTS: In univariate analysis we found that depressive symptoms as assessed by GDS were associated with both types of white matter lesions (Spearman rho = 0.12 p = 0.002 for DWML and rho = 0.09 p = 0.01 for PVL). Using ordinal logistic regression analysis the total DWML score (p = 0.041), rather than PVL (p = 0.9) was found to predict GDS scores. CONCLUSIONS: DWML, but not PVL, were most strongly associated with depressive symptoms in this sample. As DWML (unlike PVL) are associated with vascular ischaemic damage, our findings are consistent with the 'vascular depression' hypothesis. Longitudinal studies are needed to clarify the time course of these relationships, in particular, whether modifying DWML alters the natural history of depression.

White matter hyperintensities rather than lacunar infarcts are associated with depressive symptoms in older people: the LADIS study.

OBJECTIVE: Both white matter hyperintensities (WMH) and lacunar infarcts have been associated with the development of depression in older subjects, although the relative importance of the two and the influence of lesion location and concomitant vascular disease are unclear. This study investigates the relationship between location and burden of WMH and lacunes on depressive features in older people. METHOD: In a pan-European multicenter study of 626 older subjects, the authors examined the relationship between regional magnetic resonance imaging white matter hyperintensities, number of lacunar infarcts, depressive symptoms as assessed by the 15-item geriatric depression scale (GDS), cognitive status (Mini-Mental Status Examination), hypertension, and self-perceived health quality of life (QoL). RESULTS: The authors found depressive symptoms to be correlated with WMH rating in the frontal (N=626; Spearman's rho=0.161, p <0.001) and temporal (rho=0.14, p <0.001) but not occipitoparietal region (rho=0.07, p=0.07). Basal ganglia lacunes were only weakly correlated with GDS (rho=0.09, p=0.03), and lacunes in other regions showed no association. In a ordinal logistic regression model (controlling for QoL, Mini-Mental Status Examination, age, and with an interaction between WMH and hypertension), temporal WMH in the absence of hypertension independently predicted GDS, whereas neither history of stroke nor number of lacunar infarcts did. The authors compared left- versus right-sided WMH and found no effect of laterality on depressive symptoms. CONCLUSIONS: The results suggest that in this population of nondisabled older people, WMH have a greater influence on depressive symptoms than infarcts.