Effects of the COVID-19 pandemic on medication adherence: In the case of antiseizure medications, A scoping review

Since early 2020, an unprecedented public global health emergency caused by coronavirus (COVID-19) resulted in national governments' imposing confinement measures. Lockdowns and isolation during pandemics complicate disease management and medication adherence. Chronic conditions, such as epilepsy, require linear adherence patterns to prevent breakthrough seizures and to reduce the risk of sudden unexpected death. Limited access to health care facilities for routine care and medicines management further hampers this. Social isolation exacerbates stress, depression and decreases social support, which may combine to reduce adherence to antiseizure medication (ASM) during the pandemic. METHODS: We conducted a literature scoping review to explore ASM adherence among people with epilepsy, non-infected or infected SARS-CoV-2 or recovered from COVID-19 during the pandemic and explore risk factors for adherence. We search Pubmed for articles up to 16 September 2021. Search terms included the thematic of ASM adherence and COVID-19. We adhered to the PRISMA guidelines for reporting scoping reviews. RESULTS: Six articles were retained after the screening, which covered four overarching themes: change of ASM compliance and as risk factors, lack of follow-up, difficulties accessing ASM, and behavioural risk factors. Our review underscores the lack of evidence on ASM adherence among people with epilepsy infected or recovered from COVID-19. No study retrieved took place in a low-income setting, warranting a cautionary approach to be employed when extrapolating findings on a global scale. RECOMMENDATIONS FOR PRACTICE: Missing information on past SARS-CoV2 infections impact people with epilepsy precludes exploring a direct effect of SARS-CoV2 on ASM adherence. A more comprehensive chronic disease model based on the burden of co-cardiovascular and neuro-behavioural comorbidities should be envisaged for this population in preparation for future pandemics. A monitoring algorithm needs to be in place to establish a telemedicine framework and community pharmacists' potential to contribute to the model recognised

Dynamic polarity of curved aromatic soot precursors

In this paper, we answer the question of whether polar curved aromatics are persistently polar at flame temperatures. We find, using electronic structure calculations and transition state theory, that the inversion barriers of curved aromatics (cPAH) 0.9–1.2 nm in diameter are high and that they are not able to invert over the timescales and at the high temperatures found in sooting flames. We find a transition for smaller curved aromatics between 11–15 ( ≈  0.8 nm) rings where the increasing strain introduced from the pentagonal ring increases the inversion barrier leading to rigidity. We then performed ab initio quantum molecular dynamics to find the molecular dipole fluctuations of a nanometre sized cPAH at 1500 K. We found the bending mode of the bowl shaped molecule gave rise to the largest fluctuations on the dipole moment by  ± 0.5–1 debye about the equilibrium value of 5.00 debye, indicating persistent polarity. We also observed binding of a chemi-ion at 1500 K over 2 ps, suggesting the molecular dipole of cPAH will be an important consideration in soot formation mechanisms

Aromatic penta-linked hydrocarbons in soot nanoparticle formation

A new crosslinking reaction between two pentagonal rings around the periphery of planar pericondensed aromatic molecules is proposed and its impact on soot nanoparticle formation explored. The reaction mechanism was computed, using density functional theory, between an aryl-type σ-radical on arim-based pentagonal ring attacking another rim-based pentagonal ring. A hydrogen migration allowed for the formation of a double bond forming a planar aromatic penta-linked hydrocarbon (APLH) complex, recently experimentally observed. The clustering of this planar species is compared with a pericondensed polyaromatic hydrocarbon (PCAH) and an aromatic aryl-linked hydrocarbon (AALH) using molecular dynamics and metadynamics. Similar clustering is found for the investigated species compared with a peri-condensed structure of similar mass indicating enhanced physical interactions after forming the crosslink. Finally, a further crosslink is possible between the unsaturated pentagonal ring sites forming an aromatic rim-linked hydrocarbon (ARLH) complex of considerable stability. This was con firmed by simulating the stable molecular dynamics of such a complex with on-the-fly quantum forces from a quantum semi-empirical method, revealing possible reactions under ame conditions that might play a role in soot nucleation.National Research Foundation - Singapor

Polar curved polycyclic aromatic hydrocarbons in soot formation

© 2018 The Combustion Institute. In this paper, we consider the impact of polar curved polycyclic aromatic hydrocarbons (cPAH) on the process of soot formation by employing electronic structure calculations to determine the earliest onset of curvature integration and the binding energy of curved homodimers. The earliest (smallest size) onset of curvature integration was found to be a six ring PAH with at least one pentagonal ring. The σ bonding in the presence of pentagons led to curvature, however, the π bonding strongly favored a planar geometry delaying the onset of curvature and therefore the induction of a flexoelectric dipole moment. The binding energies of cPAH dimers were found to be of similar magnitude to flat PAH containing one or two pentagons, with an alignment of the dipole moments vectors. For the more curved structures, steric effects reduced the dispersion interactions to significantly reduce the interaction energy compared with flat PAH. Homogeneous nucleation of cPAH at flame temperatures then appears unlikely, however, significant interactions are expected between chemi-ions and polar cPAH molecules suggesting heterogeneous nucleation should be explored.This project is supported by the National Research Foundation (NRF), Prime Minister’s Office, Singapore under its Campus for Research Excellence and Technological Enterprise (CREATE) programme

Cancer associated auto-antibodies to MUC1 and MUC4 - A blinded case control study of colorectal cancer in UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS)

Recent reports suggest that autoantibodies directed to aberrantly glycosylated mucins, in particular MUC1 and MUC4, are found in patients with colorectal cancer. There is, however, limited information on the autoantibody levels prior to clinical diagnosis, and their utility in cancer screening in the general population. In this study, we have generated O-glycosylated synthetic MUC1 and MUC4 peptides in vitro, to mimic cancer associated glycoforms, and displayed these on microarrays. The assay's performance was tested through an initial screening of serum samples taken from patients at the time of colorectal cancer diagnosis and healthy controls. Subsequently the selected biomarkers were evaluated in a blinded nested case control study, using stored serum samples from among the 50,640 women randomised to the multimodal arm of the UKCTOCS, where women gave annual blood samples for several years. Cases were 97 postmenopausal women who developed colorectal cancer following recruitment, and were age-matched to 97 women without any history of cancer. MUC1-STn and MUC1-Core3 IgG autoantibodies identified cases with 8.2% and 13.4% sensitivity, respectively, at 95% specificity. IgA to MUC4-glycoforms were unable to discriminate between cases and controls in the UKCTOCS sera. Additional analysis was undertaken by combining the data of MUC1-STn and MUC1-Core3 with previously generated data on autoantibodies to p53 peptides, which increased the sensitivity to 32.0% at 95% specificity in the UKCTOCS set. These findings suggest that a combination of antibody signatures may have a role as part of a biomarker panel for the early detection of colorectal cancer

Reactivity of Polycyclic Aromatic Hydrocarbon Soot Precursors: Implications of Localized Radicals on Rim-Based Pentagonal Rings

This paper presents a systematic study of the reactivity of polycyclic aromatic hydrocarbons (PAH), identifying crosslinks that permit the combination of physical π-stacking interactions and covalent bonding. Hybrid density functional theory was used to identify the location of reactive sites on PAHs using the average local ionization potential. The bond energies formed between these various reactive sites were then computed. σ-Radicals were found to be the most reactive, forming bonds with other radicals and some reactive closed shell edge types. Partially saturated rim-based pentagonal rings were found to form localized π-radicals with high reactivity. This site, in addition to resonantly stabilized π-radicals, was found to be capable of bonding and stacking, which is explored for a variety of larger species. Localized π-radicals on rim-based pentagonal rings, in particular, were found to form strongly bound stacked complexes, indicating a potentially important role in soot formation

GLP-1 receptor agonists for Parkinson's disease (Review)

Background Parkinson's disease (PD) is a progressive disorder characterised by both motor and non-motor problems. Glucagon-like peptide-1 (GLP-1) receptor agonists, licensed fortreatment oftype 2 diabetes, work by stimulating GLP-1 receptors in the pancreas, which triggers the release of insulin. GLP-1 receptors have been found in the brain. Insulin signalling in the brain plays a key role in neuronal metabolism and repair and in synaptic eEicacy, but insulin signalling is desensitised in the brain of people with PD. Researchers are exploring the neuroprotective effects of GLP-1 receptor agonists in neurodegenerative disorders such as PD. Objectives To evaluate the eEectiveness and safety of GLP-1 receptor agonists for Parkinson's disease. Search methods We searched the Cochrane Movement Disorders Group trials register; the Cochrane Central Register of Controlled Trials (CENTRAL), in the Cochrane Library; and Ovid MEDLINE and Embase. We also searched clinical trials registries, and we handsearched conference abstracts. The most recent search was run on 25 June 2020. Selection criteria We included randomised controlled trials (RCTs) of adults with PD that compared GLP-1 receptor agonists with conventional PD treatment, placebo, or no treatment. Data collection and analysis Two reviewauthors independently assessed studies forinclusion, extracted data, and assessed risk of bias.We rated the quality of evidence using GRADE. We resolved discrepancies between the two data extractors by consultation with a third review author. Main results Through our searches, we retrieved 99 unique records, of which two met ourinclusion criteria. One double-blind study of exenatide versus placebo randomised 62 participants, who self-administered exenatide or placebo for 48 weeks and were followed up at 60 weeks after a 12-week washout. One single-blind study of exenatide versus no additional treatment randomised 45 participants; participants in the intervention group self-administered exenatide for 12 months, and all participants were followed up at 14 months and 24 months following absence of exenatide for 2 months and 12 months, respectively. These trials had low risk of bias, except risk of performance bias was high for Aviles-Olmos 2013. Exenatide versus placebo Primary outcomes We found low-certainty evidence suggesting that exenatide improves motor impairment as assessed by the Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part III in the oE-medication state (mean difference (MD) -3.10, 95% confidence interval (CI) -6.11 to -0.09). The diEerence in scores was slightly greater when scores were adjusted for baseline severity of the condition (as reported by study authors) (MD -3.5, 95% CI -6.7 to -0.3), exceeding the minimum clinically important difference (MCID). We found low-certainty evidence suggesting that exenatide has little or no eEect on health-related quality of life (HRQoL) as assessed by the Parkinson's Disease Questionnaire (PDQ)-39 Summary Index (SI) (MD -1.80, 95% CI -6.95 to 3.35), the EuroQol scale measuring health status in five dimensions (EQ5D) (MD 0.07, 95% CI -0.03 to 0.16), or the EQ5D visual analogue scale (VAS) (MD 5.00, 95% CI -3.42 to 13.42). Eight serious adverse events (SAEs) were recorded, but all were considered unrelated to the intervention. Low-certainty evidence suggests that exenatide has little or no effect on weight loss (risk ratio (RR) 1.25, 95% CI 0.89 to 1.76). Exenatide versus no treatment Primary outcomes at 14 months We found very low-certainty evidence suggesting that exenatide improves motor impairment as assessed by MDS-UPDRS Part III off medication (MD -4.50, 95% CI -8.64 to -0.36), exceeding the MCID. We are uncertain whether exenatide improves HRQoL as assessed by the PDQ-39 SI (MD 3.50, 95% CI -2.75 to 9.75; very low-quality evidence). We found very low-certainty evidence suggesting that exenatide has little or no eEect on the number of SAEs (RR 1.60, 95% 0.40 to 6.32). We found very low-certainty evidence suggesting that exenatide may lead to weight loss (MD -2.40 kg, 95% CI -4.56 to -0.24). Primary outcomes at 24 months We found evidence as reported by study authors to suggest that exenatide improves motor impairment as measured by MDS-UPDRS Part III off medication (MD 5.6 points, 95% CI 2.2 to 9.0). Exenatide may not improve HRQoL as assessed by the PDQ-39 SI (P = 0.682) and may not result in weight loss (MD 0.1 kg, 95% CI 3.0 to 2.8). Authors' conclusions Low- or very low-certainty evidence suggests that exenatide may improve motor impairment for people with PD. The difference in motor impairment observed between groups may persistfor some time following cessation of exenatide. This raises the possibility that exenatide may have a disease-modifying eEect. SAEs were unlikely to be related to treatment. The eEectiveness of exenatide for improving HRQoL, non-motor outcomes, ADLs, and psychological outcomes is unclear. Ongoing studies are assessing other GLP-1 receptor agonists

Delivery of sTRAIL variants by MSCs in combination with cytotoxic drug treatment leads to p53-independent enhanced antitumor effects

Mesenchymal stem cells (MSCs) are able to infiltrate tumor tissues and thereby effectively deliver gene therapeutic payloads. Here, we engineered murine MSCs (mMSCs) to express a secreted form of the TNF-related apoptosis-inducing ligand (TRAIL), which is a potent inducer of apoptosis in tumor cells, and tested these MSCs, termed MSC.sTRAIL, in combination with conventional chemotherapeutic drug treatment in colon cancer models. When we pretreated human colorectal cancer HCT116 cells with low doses of 5-fluorouracil (5-FU) and added MSC.sTRAIL, we found significantly increased apoptosis as compared with single-agent treatment. Moreover, HCT116 xenografts, which were cotreated with 5-FU and systemically delivered MSC.sTRAIL, went into remission. Noteworthy, this effect was protein 53 (p53) independent and was mediated by TRAIL-receptor 2 (TRAIL-R2) upregulation, demonstrating the applicability of this approach in p53-defective tumors. Consequently, when we generated MSCs that secreted TRAIL-R2-specific variants of soluble TRAIL (sTRAIL), we found that such engineered MSCs, labeled MSC.sTRAIL DR5, had enhanced antitumor activity in combination with 5-FU when compared with MSC.sTRAIL. In contrast, TRAIL-resistant pancreatic carcinoma PancTu1 cells responded better to MSC.sTRAIL DR4 when the antiapoptotic protein XIAP (X-linked inhibitor of apoptosis protein) was silenced concomitantly. Taken together, our results demonstrate that TRAIL-receptor selective variants can potentially enhance the therapeutic efficacy of MSC-delivered TRAIL as part of individualized and tumor-specific combination treatments. © 2013 Macmillan Publishers Limited All rights reserved