Now showing items 669-688 of 1026

• #### N-3 fatty acid supplementation mediates lipid profile, including small dense LDL, when combined with statins: a randomized double blind placebo controlled trial.

Epidemiological and clinical evidence suggests that high-dose intake of omega 3 fatty acids (n-3 FA) have a favorable role in altering serum triglycerides (TG) and non-high density lipoprotein cholesterol (non-HDL-C) when combined with statins in hyperlipidemic patients. Their efficacy in altering low-density lipoprotein cholesterol (LDL-C) particle size is yet to be established. This study evaluated the effects of supplementing 4 g/day Eicosapentaenoic acid (EPA) and Docosahexaenoic acid (DHA) on serum blood lipids, including small, dense LDL-C particle concentration, in hyperlipidemic patients receiving stable statin therapy. In this randomized, placebo-controlled, double-blind parallel group study, 44 patients on statin therapy for > 8 weeks with non-HDL-C concentrations above 130 mg/dL were randomized into two groups. For 8 weeks, together with their prescribed statin, the intervention group received 4 g/day EPA + DHA (3000 mg EPA + 1000 mg DHA in ethyl ester form) and the placebo group received 4 g/day olive oil (OO). Measurements of serum non-HDL-C, TG, total cholesterol (TC), high density lipoprotein cholesterol (HDL-C), LDL-C (including large - LDL I; intermediate - LDL II; and small - LDL III subclasses), very-low-density lipoprotein cholesterol (VLDL-C) concentration, were taken at baseline and post-intervention. Dietary intake was assessed with a weighed intake, 3-day food diary at week 4. Primary outcome measures were percent change in LDL III, non-HDL-C and LDL particle number. At the end of treatment, the median percent change in serum LDL III concentration was significantly greater in the n-3 FA group plus atorvastatin compared to placebo (- 67.5% vs - 0%, respectively; P < 0.001). Supplementation with n-3 FA plus atorvastatin led to significant reductions in serum non-HDL-C (- 9.5% vs 4.7%, P < 0.01), TG (- 21.5% vs 6.2%, P < 0.001) and VLDL-C (- 36.9% vs 4.0%, P < 0.001) and TC (- 6.6% vs 2.1%, P < 0.001). Between the groups, no significant difference in percent change in the serum concentration of LDL-C, HDL-C, as well as in the LDL I and LDL II subclasses was observed. In this group of hyperlipidemic patients on a stable statin prescription, OM3 plus atorvastatin improved small dense LDL concentrations, non-HDL-C, VLDL-C and TG to a greater extent than atorvastatin alone. Further studies are warranted in this area. This trial was retrospectively registered on 23 May 2019 on ClinicalTrials.gov with ID: NCT03961763. [Abstract copyright: © 2022. The Author(s).]
• #### Nanometre imaging of Fe 3 GeTe 2 ferromagnetic domain walls

Abstract: Fe3GeTe2 is a layered crystal which has recently been shown to maintain its itinerant ferromagnetic properties even when atomically thin. Here, differential phase contrast scanning transmission electron microscopy is used to investigate the domain structure in a Fe3GeTe2 cross-sectional lamella at temperatures ranging from 95 to 250 K and at nanometre spatial resolution. Below the experimentally determined Curie temperature (T C) of 191 K, stripe domains magnetised along 〈0001〉, bounded with 180◦ Bloch type domain walls, are observed, transitioning to mixed Bloch−Néel type where the cross-sectional thickness is reduced below 50 nm. When warming towards T C, these domains undergo slight restructuring towards uniform size, before abruptly fading at T C. Localised loss of ferromagnetic order is seen over time, hypothesised to be a frustration of ferromagnetic order from ambient oxidation and basal cracking, which could enable selective modification of the magnetic properties for device applications.
• #### Nanometre imaging of Fe 3 GeTe 2 ferromagnetic domain walls

Abstract: Fe3GeTe2 is a layered crystal which has recently been shown to maintain its itinerant ferromagnetic properties even when atomically thin. Here, differential phase contrast scanning transmission electron microscopy is used to investigate the domain structure in a Fe3GeTe2 cross-sectional lamella at temperatures ranging from 95 to 250 K and at nanometre spatial resolution. Below the experimentally determined Curie temperature (T C) of 191 K, stripe domains magnetised along 〈0001〉, bounded with 180◦ Bloch type domain walls, are observed, transitioning to mixed Bloch−Néel type where the cross-sectional thickness is reduced below 50 nm. When warming towards T C, these domains undergo slight restructuring towards uniform size, before abruptly fading at T C. Localised loss of ferromagnetic order is seen over time, hypothesised to be a frustration of ferromagnetic order from ambient oxidation and basal cracking, which could enable selective modification of the magnetic properties for device applications.
• #### National Health Service interventions in England to improve care to Armed Forces veterans

Armed Forces veterans (AFVs) are first and foremost citizens of the UK and are therefore—like all UK residents—entitled to universal healthcare, free at the point of need. This means that AFVs have nearly all their healthcare needs met by the NHS, which provides access to a full range of generic services. However, since 2013 there has been an Armed Forces team that can also support veterans. This review is an assessment of the work of this group over the last eight years. The health needs of AFVs have been investigated and are not significantly different from those of their demographically matched peers. However, due to their demographics, selection at recruitment and their roles, AFVs compared with the general population are more likely to be male, white and old and have fewer pre-existing or hereditary conditions. However, they do suffer from higher rates of musculoskeletal injury, different patterns of mental health illness and have historically been higher users—and abusers—of alcohol and tobacco. In addition to supporting mainstream services used by AFVs, the NHS in England commissions a bespoke range-specific ‘Priority’ NHS services such as those for mental health or for rehabilitation of veterans using prostheses. New interventions are continuing to be developed to improve AFVs’ healthcare and are aligned to the NHS Long Term Plan and the restoration and recovery plans after the COVID-19 pandemic.
• #### Neferine induces autophagy-dependent cell death in apoptosis-resistant cancers via ryanodine receptor and Ca 2+ -dependent mechanism

Abstract: Resistance of cancer cells to chemotherapy is a significant clinical concern and mechanisms regulating cell death in cancer therapy, including apoptosis, autophagy or necrosis, have been extensively investigated over the last decade. Accordingly, the identification of medicinal compounds against chemoresistant cancer cells via new mechanism of action is highly desired. Autophagy is important in inducing cell death or survival in cancer therapy. Recently, novel autophagy activators isolated from natural products were shown to induce autophagic cell death in apoptosis-resistant cancer cells in a calcium-dependent manner. Therefore, enhancement of autophagy may serve as additional therapeutic strategy against these resistant cancers. By computational docking analysis, biochemical assays, and advanced live-cell imaging, we identified that neferine, a natural alkaloid from Nelumbo nucifera, induces autophagy by activating the ryanodine receptor and calcium release. With well-known apoptotic agents, such as staurosporine, taxol, doxorubicin, cisplatin and etoposide, utilized as controls, neferine was shown to induce autophagic cell death in a panel of cancer cells, including apoptosis-defective and -resistant cancer cells or isogenic cancer cells, via calcium mobilization through the activation of ryanodine receptor and Ulk-1-PERK and AMPK-mTOR signaling cascades. Taken together, this study provides insights into the cytotoxic mechanism of neferine-induced autophagy through ryanodine receptor activation in resistant cancers.
• #### Neuropsychiatric symptoms following metal-on-metal implant failure with cobalt and chromium toxicity

Background: There were at least 31,171 metal-on-metal (MoM) hip implants in the UK between 2003 and 2011. Some of these were subject to failure and widescale recalls and revisions followed. Method This is a presentation of ten cases (mean age 60 years) where we evaluated neuropsychiatric morbidity following metal-on-metal hip implant failure and revision. Implants were ASR total hip replacement (acetabular implant, taper sleeve adaptor and unipolar femoral implants) performed between 2005 and 2009. This case series describes, for the first time, neuropsychiatric complications after revision where there has been cobalt and chromium toxicity. Results Pre-revision surgery, nine patients had toxic levels of chromium and cobalt (mean level chromium 338 nmol/l, mean cobalt 669.4 nmol/l). Depression assessment showed 9 of 9 respondents fulfilled the BDI criteria for depression and 3 of these were being treated. 7 of 9 patients showing short term memory deficit with mean mini mental state examination score of 24.2. The normal population mean MMSE for this group would be expected to be 28 with <25 indicating possible dementia. Conclusions We found neurocognitive and depressive deficits after cobalt and chromium metallosis following MoM implant failure. Larger studies of neurocognitive effects are indicated in this group. There may be implications for public health.
• #### Neutrally charged self-assembling peptide hydrogel recapitulates in vitro mechanisms of breast cancer progression.

Self-assembling peptide hydrogels (SAPH) are a popular biomaterial due to their biocompatibility with a wide range of cell types, synthetic design, structural properties that provide a more accurate 3D microenvironment, and potential for cell- and/or drug-delivery system. Mimicking solid tumors in vitro using hydrogels is one method of testing anti-cancer drug efficacy and observing cancerous cell-ECM interactions within a 3D system. In this study, a SAPH, PeptiGel®Alpha1, was used to model in vitro the 3D breast tumor microenvironment. PeptiGel®Alpha1 is composed of entangled nanofibers with consistent diameter and mechanical properties similar to breast cancer that more accurately mimic the stiffness of breast tumor tissue than Matrigel® or collagen type I. PeptiGel®Alpha1 supported the viability and growth of the breast cancer cell lines MCF-7 and MDA-MB-231 and recapitulated key features of solid tumors such as hypoxia and invasion. MCF-7 cells in the hydrogels formed large spheroids resembling acini, while MDA-MB-231 remained dispersed. When treated with tamoxifen, PeptiGel®Alpha1 acted as a barrier, providing drug penetration geometry similar to that in vivo, providing better prediction of the drug effect. Finally, it was observed that MCF-7 cells engulfed the peptide matrix after 14 days, highlighting a potential use in drug delivery. PeptiGel®Alpha1 is a suitable platform for in vitro modeling of breast cancer. [Abstract copyright: Copyright © 2021. Published by Elsevier B.V.]
• #### New extremal binary self-dual codes from block circulant matrices and block quadratic residue circulant matrices

In this paper, we construct self-dual codes from a construction that involves both block circulant matrices and block quadratic residue circulant matrices. We provide conditions when this construction can yield self-dual codes. We construct self-dual codes of various lengths over F 2 and F 2 + u F 2 . Using extensions, neighbours and sequences of neighbours, we construct many new self-dual codes. In particular, we construct one new self-dual code of length 66 and 51 new self-dual codes of length 68.
• #### New insights into Perrault syndrome, a clinically and genetically heterogeneous disorder.

Hearing loss and impaired fertility are common human disorders each with multiple genetic causes. Sometimes deafness and impaired fertility, which are the hallmarks of Perrault syndrome, co-occur in a person. Perrault syndrome is inherited as an autosomal recessive disorder characterized by bilateral mild to severe childhood sensorineural hearing loss with variable age of onset in both sexes and ovarian dysfunction in females who have a 46, XX karyotype. Since the initial clinical description of Perrault syndrome 70 years ago, the phenotype of some subjects may additionally involve developmental delay, intellectual deficit and other neurological disabilities, which can vary in severity in part dependent upon the genetic variants and the gene involved. Here, we review the molecular genetics and clinical phenotype of Perrault syndrome and focus on supporting evidence for the eight genes (CLPP, ERAL1, GGPS1, HARS2, HSD17B4, LARS2, RMND1, TWNK) associated with Perrault syndrome. Variants of these eight genes only account for approximately half of the individuals with clinical features of Perrault syndrome where the molecular genetic base remains under investigation. Additional environmental etiologies and novel Perrault disease-associated genes remain to be identified to account for unresolved cases. We also report a new genetic variant of CLPP, computational structural insight about CLPP and single cell RNAseq data for eight reported Perrault syndrome genes suggesting a common cellular pathophysiology for this disorder. Some unanswered questions are raised to kindle future research about Perrault syndrome. [Abstract copyright: © 2021. This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.]
• #### New singly and doubly even binary [72,36,12] self-dual codes from M 2(R)G - group matrix rings

In this work, we present a number of generator matrices of the form [ I 2 n | τ 2 ( v ) ] , where I 2 n is the 2 n × 2 n identity matrix, v is an element in the group matrix ring M 2 ( R ) G and where R is a finite commutative Frobenius ring and G is a finite group of order 18. We employ these generator matrices and search for binary [ 72 , 36 , 12 ] self-dual codes directly over the finite field F 2 . As a result, we find 134 Type I and 1 Type II codes of this length, with parameters in their weight enumerators that were not known in the literature before. We tabulate all of our findings.
• #### New Technique to Improve the Ductility of Steel Beam to Column Bolted Connections: A Numerical Investigation

A novel method to improve the robustness of steel end plate connections is presented in this paper. Existing commonly adopted techniques alter the stiffness of the beam or the end plate to improve the connection’s robustness. In this study, the robustness is enhanced by improving the contribution of the bolts to the rotational capacity of connections; the higher the bolts’ elongation, the higher the rotational capacity that can be achieved. However, the brittleness of the bolt material, combined with its small length, results in negligible elongation. Alternatively, the load path between the end plate and the bolts can be interrupted with a ductile element to achieve the required elongation. This can be achieved by inserting a steel sleeve with a designated length, thickness, and wall curvature between the end plate and the washer. The proposed sleeve should be designed so that its ultimate capacity is less than the force in the bolt at failure; accordingly, the sleeve develops a severe bending deformation before the failure of any connection components. Using a validated finite element model, end plate connections with various parameters are numerically investigated to understand the performance of the sleeve device. The proposed system substantially enhances the rotational capacity of the connections, ranging between 1.37 and 2.46 times that of the standard connection. It is also concluded that the sleeved connections exhibit a consistent elastic response with the standard connections, indicating the proposed system is compatible with codified elastic design approaches without modification. Furthermore, for a specific connection, various ductile responses can be achieved without altering the connection capacity nor configuration.
• #### New type I binary $[72, 36, 12]$ self-dual codes from $M_6(\mathbb{F}_2)G$ - Group matrix rings by a hybrid search technique based on a neighbourhood-virus optimisation algorithm

&lt;p style='text-indent:20px;'&gt;In this paper, a new search technique based on a virus optimisation algorithm is proposed for calculating the neighbours of binary self-dual codes. The aim of this new technique is to calculate neighbours of self-dual codes without reducing the search field in the search process (this technique is known in the literature due to the computational time constraint) but still obtaining results in a reasonable time (significantly faster when compared to the standard linear computational search). We employ this new search algorithm to the well-known neighbour method and its extension, the &lt;inline-formula&gt;&lt;tex-math id="M1"&gt;\begin{document}$k^{th}$\end{document}&lt;/tex-math&gt;&lt;/inline-formula&gt;-range neighbours, and search for binary &lt;inline-formula&gt;&lt;tex-math id="M2"&gt;\begin{document}$[72, 36, 12]$\end{document}&lt;/tex-math&gt;&lt;/inline-formula&gt; self-dual codes. In particular, we present six generator matrices of the form &lt;inline-formula&gt;&lt;tex-math id="M3"&gt;\begin{document}$[I_{36} \ | \ \tau_6(v)],$\end{document}&lt;/tex-math&gt;&lt;/inline-formula&gt; where &lt;inline-formula&gt;&lt;tex-math id="M4"&gt;\begin{document}$I_{36}$\end{document}&lt;/tex-math&gt;&lt;/inline-formula&gt; is the &lt;inline-formula&gt;&lt;tex-math id="M5"&gt;\begin{document}$36 \times 36$\end{document}&lt;/tex-math&gt;&lt;/inline-formula&gt; identity matrix, &lt;inline-formula&gt;&lt;tex-math id="M6"&gt;\begin{document}$v$\end{document}&lt;/tex-math&gt;&lt;/inline-formula&gt; is an element in the group matrix ring &lt;inline-formula&gt;&lt;tex-math id="M7"&gt;\begin{document}$M_6(\mathbb{F}_2)G$\end{document}&lt;/tex-math&gt;&lt;/inline-formula&gt; and &lt;inline-formula&gt;&lt;tex-math id="M8"&gt;\begin{document}$G$\end{document}&lt;/tex-math&gt;&lt;/inline-formula&gt; is a finite group of order 6, to which we employ the proposed algorithm and search for binary &lt;inline-formula&gt;&lt;tex-math id="M9"&gt;\begin{document}$[72, 36, 12]$\end{document}&lt;/tex-math&gt;&lt;/inline-formula&gt; self-dual codes directly over the finite field &lt;inline-formula&gt;&lt;tex-math id="M10"&gt;\begin{document}$\mathbb{F}_2$\end{document}&lt;/tex-math&gt;&lt;/inline-formula&gt;. We construct 1471 new Type I binary &lt;inline-formula&gt;&lt;tex-math id="M11"&gt;\begin{document}$[72, 36, 12]$\end{document}&lt;/tex-math&gt;&lt;/inline-formula&gt; self-dual codes with the rare parameters &lt;inline-formula&gt;&lt;tex-math id="M12"&gt;\begin{document}$\gamma = 11, 13, 14, 15, 17, 19, 20, 21, 22, 23, 25, 26, 28, 29, 30, 31, 32$\end{document}&lt;/tex-math&gt;&lt;/inline-formula&gt; in their weight enumerators.&lt;/p&gt;

• #### “No Way Out Except From External Intervention”: First-Hand Accounts of Autistic Inertia

This study, called for by autistic people and led by an autistic researcher, is the first to explore ‘autistic inertia,’ a widespread and often debilitating difficulty acting on their intentions. Previous research has considered initiation only in the context of social interaction or experimental conditions. This study is unique in considering difficulty initiating tasks of any type in real life settings, and by gathering qualitative data directly from autistic people. Four face-to-face and 2 online (text) focus groups were conducted with 32 autistic adults (19 female, 8 male, and 5 other), aged 23–64 who were able to express their internal experiences in words. They articulate in detail the actions they have difficulty with, what makes it easier or harder to act, and the impact on their lives. Thematic analysis of the transcripts found four overarching themes: descriptions of inertia, scaffolding to support action, the influence of wellbeing, and the impact on day-to-day activities. Participants described difficulty starting, stopping and changing activities that was not within their conscious control. While difficulty with planning was common, a subset of participants described a profound impairment in initiating even simple actions more suggestive of a movement disorder. Prompting and compatible activity in the environment promoted action, while mental health difficulties and stress exacerbated difficulties. Inertia had pervasive effects on participants’ day-to-day activities and wellbeing. This overdue research opens the door to many areas of further investigation to better understand autistic inertia and effective support strategies.
• #### Non-Newtonian Droplet Generation in a Cross-Junction Microfluidic Channel

A two-dimensional CFD model based on volume-of-fluid (VOF) is introduced to examine droplet generation in a cross-junction microfluidic using an open-source software, OpenFOAM together with an interFoam solver. Non-Newtonian power-law droplets in Newtonian liquid is numerically studied and its effect on droplet size and detachment time in three different regimes, i.e., squeezing, dripping and jetting, are investigated. To understand the droplet formation mechanism, the shear-thinning behaviour was enhanced by increasing the polymer concentrations in the dispersed phase. It is observed that by choosing a shear-dependent fluid, droplet size decreases compared to Newtonian fluids while detachment time increases due to higher apparent viscosity. Moreover, the rheological parameters—n and K in the power-law model—impose a considerable effect on the droplet size and detachment time, especially in the dripping and jetting regimes. Those parameters also have the potential to change the formation regime if the capillary number (Ca) is high enough. This work extends the understanding of non-Newtonian droplet formation in microfluidics to control the droplet characteristics in applications involving shear-thinning polymeric solutions.

• #### Not only laboratory to clinic: the translational work of William S. C. Copeman in rheumatology

Abstract: Since the arrival of Translational Medicine (TM), as both a term and movement in the late 1990s, it has been associated almost exclusively with attempts to accelerate the “translation” of research-laboratory findings to improve efficacy and outcomes in clinical practice (Krueger et al. in Hist Philos Life Sci 41:57, 2019). This framing privileges one source of change in medicine, that from bench-to-bedside. In this article we dig into the history of translation research to identify and discuss three other types of translational work in medicine that can also reshape ideas, practices, institutions, behaviours, or all of these, to produce transformations in clinical effectiveness. These are: (1) making accessible state-of-the-art knowledge and best practice across the medical profession; (2) remodelling and creating institutions to better develop and make available specialist knowledge and practice; and (3) improving public and patient understandings of disease prevention, symptoms and treatments. We do so by examining the work of William S. C. Copeman, a dominant figure in British rheumatology from the 1930 through the late 1960s. Throughout his long career, Copeman blended approaches to “translation” in order to produce transformative change in clinical medicine, making his work an exemplar of our expanded notion of TM.
• #### Notch Signalling in Breast Development and Cancer

The Notch signalling pathway is a highly conserved developmental signalling pathway, with vital roles in determining cell fate during embryonic development and tissue homeostasis. Aberrant Notch signalling has been implicated in many disease pathologies, including cancer. In this review, we will outline the mechanism and regulation of the Notch signalling pathway. We will also outline the role Notch signalling plays in normal mammary gland development and how Notch signalling is implicated in breast cancer tumorigenesis and progression. We will cover how Notch signalling controls several different hallmarks of cancer within epithelial cells with sections focussed on its roles in proliferation, apoptosis, invasion, and metastasis. We will provide evidence for Notch signalling in the breast cancer stem cell phenotype, which also has implications for therapy resistance and disease relapse in breast cancer patients. Finally, we will summarise the developments in therapeutic targeting of Notch signalling, and the pros and cons of this approach for the treatment of breast cancer.