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Amyloid-β antibodies were modified to incorporate trans-cyclooctene functional groups. Radiolabeled copper-64 probes, which can cross the blood–brain barrier and contain a 1,2,4,5-tetrazine functional group, react with the modified antibodies.

Sensitivity analysis.

NICE guidelines.

In the United Kingdom, women at moderate and high risk of breast cancer between the ages of 40 and 49 years are eligible for annual mammographic screening and preventive therapy with tamoxifen. Here, we estimate the numbers of women in a population eligible for this service and the proportion of breast cancers detected in this group compared with the whole population. Women N = 384), but the numbers of cancers in this group were not appreciably increased (N = 8). Systematic assessment of family history in primary care or through population-based screening will identify appreciable numbers of women in their forties, eligible for additional surveillance and chemoprevention Cancer Prev Res; 7(10); 993–1001. ©2014 AACR.

P-glycoprotein (P-gp) is an efflux transporter at the blood-brain barrier (BBB) that hinders brain access of substrate drugs and clears endogenous molecules such as amyloid beta (Aβ) from the brain. As biometals such as copper (Cu) modulate many neuronal signalling pathways linked to P-gp regulation, it was hypothesised that the bis(thiosemicarbazone) (BTSC) Cu-releasing complex, copper II glyoxal bis(4-methyl-3-thiosemicarbazone) (Cu

The synthesis and structural characterisation of an icosanuclear silver(I) cluster complex is reported here. The complex includes twenty silver(I) ions supported by eighteen bis(thiosemicarbazonato) ligands. The cluster of silver(I) ions involves several close Ag⋯Ag contacts suggesting some degree of argentophilic interactions and the bis(thiosemicarbazonato) ligands are present in three different conformations highlighting the ability of thiosemicarbazone ligands to coordinate to metal ions in different modes.

The gas-phase extrusion–insertion (ExIn) reactions of a silver complex [(BPS)Ag(O2CC6H5)]2− ([BPS]2− = 4,7-diphenyl-1,10-phenanthroline-disulfonate), generated via electrospray ionisation was investigated by Multistage Mass Spectrometry (MSn ) experiments in a linear ion trap combined with density functional theory (DFT) calculations. Extrusion of carbon dioxide under collision-induced dissociation (CID) generates the organosilver intermediate [(BPS)Ag(C6H5)]2−, which subsequently reacts with phenyl isocyanate via insertion to yield [(BPS)Ag(NPhC(O)C6H5)]2−. Further CID of the product ion resulted in the formation of [(BPS)Ag(C6H5)]2−, [(BPS)Ag]− and C6H5C(O)NPh−. The formation of a coordinated amidate anion is supported by DFT calculations. Heating a mixture of benzoic acid, phenyl isocyanate, silver carbonate (5 mol%) and phenanthroline (20 mol%) in DMSO and heating by microwave irradiation led to the formation N-phenyl-benzamide in an isolated yield of 89%. The yield decreased to 74% without the addition of phenanthroline, while replacing silver carbonate with sodium carbonate gave an isolated yield of 84%, suggesting that the ExIn reaction may not operate in solution. This was confirmed using benzoic acid with a 13C-isotopic-label at the carboxylate carbon as the starting material, which, under microwave heating in the presence of phenyl isocyanate, silver carbonate (5 mol%) and phenanthroline (20 mol%) gave N-phenyl-benzamide with retention of the 13C isotopic label based on GC-MS experiments under electron ionisation (EI) conditions. DFT calculations using a solvent continuum reveal that the barriers associated with the pathway involving direct attack by the non-coordinated benzoate are below the ExIn pathways for the coordinated silver benzoate.

The syntheses of non-oxido/non-nitrido bis(thiosemicarbazonato)technetium(V) complexes featuring a series of alkyl and ether substituents is presented. The bis(thiosemicarbazones) were radiolabelled with technetium-99m using an optimised one-pot synthesis from [

The preparation of Co(ii) and Co(iii) SALPN type catalysts for the Mukaiyama hydration of enones, and their application to the synthesis of acyloin natural products is described. An acyloin rearrangement was key to the success of this approach.

Spatial discretization of biomolecules in the complex cellular environment is crucial for biomolecular form and function. The ability to better understand the driving force of spatial discretization of biomolecules in the complex cellular matrix remains a challenging task. We report on the robust polarity sensitive solvatochromic probe,FLAM, in conjunction with spectral phasor analysis as a general method for studying environmental polarity in biological systems. We find that phase separated proteins of SFPQ have distinct polarity depending on the type of phase separation occurring, suggesting that polarity plays a role in the formation of phase separated condensates. When usingFLAMin cells, distinct subcellular environmental polarity distribution but similar trend of changes is observed for cells under similar type of stressors. Taken together, our method puts forth an exciting development in the tool set for the study of phase separation.

Preliminary explorations of the annihilation electrogenerated chemiluminescence (ECL) of mixed metal complexes have revealed opportunities to enhance emission intensities and control the relative intensities from multiple luminophores through the applied potentials. However, the mechanisms of these systems are only poorly understood. Herein, we present a comprehensive characterisation of the annihilation ECL of mixtures of tris(2,2'-bipyridine) ruthenium(II) hexafluorophosphate ([Ru(bpy)(3)](PF6)(2)) and fac-tris(2-phenylpyridine)iridium(III) ([Ir(ppy)(3)]). This includes a detailed investigation of the change in emission intensity from each luminophore as a function of both the applied electrochemical potentials and the relative concentrations of the two complexes, and a direct comparison with two mixed (Ru/Ir) ECL systems for which emission from only the ruthenium-complex was previously reported. Concomitant emission from both luminophores was observed in all three systems, but only when: (1) the applied potentials were sufficient to generate the intermediates required to form the electronically excited state of both complexes; and (2) the concentration of the iridium complex (relative to the ruthenium complex) was sufficient to overcome quenching processes. Both enhancement and quenching of the ECL of the ruthenium complex was observed, depending on the experimental conditions. The observations were rationalised through several complementary mechanisms, including resonance energy transfer and various energetically favourable electron-transfer pathways. Refereed/Peer-reviewed

Background Robotics is now seen as part of the solution to the ageing population internationally, and is deployed in care settings. Care robots are designed to enable active ageing as well as ageing in place, with support to older persons, their families, and care professionals. The aim of this study was to understand the perceptions of stakeholders in Hong Kong and Ireland regarding the current state of affairs surrounding the use of care robots in their jurisdictions. Methods Semi-structured, in-depth interviews were conducted with 30 experts (15 from each jurisdiction). The participants included care professionals, service providers, researchers, and advocacy group representatives and policymakers. The questions explored their knowledge of and perceptions regarding the current use of assistive technologies, long-term care systems, and their own future vision of care provision for old age. Results In both jurisdictions, the use of care robots is relatively new, although many respondents were familiar with the seal robot PARO and the humanoid robot Pepper. In Hong Kong, a gerontechnology-specific exposition has become an annual feature in recent years, and the government’s investment has stepped up. In Ireland, a more general ehealth agenda has been adopted within the government’s planned care reform (Sláintecare). Older people in Hong Kong and Ireland are believed to fall through the cracks in their respective two-tier care systems, and many respondents stated that care robots are most needed in order to fill the gaps (e.g. safety monitoring, mobility support). Concerns regarding the impact of using robots included a possible reduction in human-to-human contact and deskilling of older people themselves. Conclusion There was a sense of urgency in both jurisdictions that more smart and digital technologies should be utilised to ease the pressures on care professionals and systems. However, a degree of optimism was noted for technological leapfrogging after the pandemic.

Background Fundamental to the successful delivery of integrated care for older people in Ireland and internationally, is sustainable interprofessional collaboration (IPC). Current evidence, however, offers little guidance in terms of how IPC can be fostered and sustained within the context of integrated care and older people. This research aimed to design a framework that describes core competencies for IPC within integrated care teams (ICTs) for older people, and outline mechanisms by which ICTs could start to develop the necessary knowledge, skills and behaviours to demonstrate proficiency. Methods Using a co-design approach, academic health systems researchers, members of the National Integrated Care Programme for Older People in Ireland (IPC subcommittee), and public and patient representatives (nominated by Age Friendly Ireland) collaborated across three studies to devise a core competency framework. Study 1 used co-design workshops to develop and gain consensus on core competencies; study 2 employed semi-structured interviews to explore current working practice within two existing interprofessional ICTs and study 3, combined findings from study 1 and 2, validated the agreed upon competencies and finalised the IPC competency framework. Results Six competencies, within three domains, were agreed. Domain one, knowledge of the team, includes the competencies, understanding roles and making referrals. Domain two, communication, includes sharing information and communicating effectively and domain three, shared decision-making, includes the final two competencies, supporting decision making with older people and collective clinical decision-making. Conclusion This co-designed framework provides the scaffold for curriculum development for the training of health and social care professionals around interdisciplinary team working for the care of older people. The core competencies prioritise mutual respect and active elicitation of input from all disciplines, thereby empowering disciplinary-specific expertise. Finally, and perhaps most critically, the will and preferences of the older person are deemed central to effective integrated interprofessional working within the developed IPC framework.

Background The investigation of, and interventions on, the alleged abuse of vulnerable adults, including older people,has become an important feature of social work.Policy and practice in adult safeguarding is characterised by competing debates about how regulators define core concepts and reporting systems. It has been argued that the introduction of specialist legislation could enhance responses to adult safeguarding (Montgomery et al.2016). This study sets out to shed light on how social work practitioners are navigating cases in the absence of primary legislation and to explore what benefits or challenges there might be should adult safeguarding legislation be fully enacted in the Irish context. Methods Focus Groups (N = 2) and face to face interviews (N = 14) were held with social work practitioners using a critical incident technique.An online survey questionnaire was also administered with N = 116 responses. Results Social workers reported that adults at risk were ‘falling through the cracks’ due to the absence of adult safeguarding legislation. In relation to older people, the issue of coercive control by another family member was repeatedly highlighted as a significant issue for which there was no legislative intervention available. Legislative powers such as a duty to cooperate, duty to share information and a duty to involve the adult at risk in the safeguarding process were deemed critically important but absent. In addition, social workers reported that the lack of access to support services for the adult at risk was significantly impacting on their ability to safeguard. Conclusion Whilst the current policy measures in place offer some protection, it is evident that social work practitioners believe that safeguarding procedures should be placed on a statutory basis to ensure the safeguarding process is applied in a consistent and effective way. Reference Montgomery, L., Anand, J., McKay, K., Taylor, B., Pearson, K. C., & Harper, C. M. (2016). Implications of divergences in Adult Protection legislation. Journal of Adult Protection, 18(3).

Background Providing women with personalized estimates of their risk of developing breast cancer, as part of routine breast cancer screening programmes, allows women at higher risk to be offered more frequent screening or drugs to reduce risk. For this to be feasible, the concept and practicalities have to be acceptable to the healthcare professionals who would put it in to practice. The present research investigated the acceptability to healthcare professionals who were responsible for the implementation of this new approach to screening in the ongoing BC-Predict study. Methods Four focus groups were conducted with 29 healthcare professionals from a variety of professional backgrounds working within three breast screening services in north-west England. An inductive-manifest thematic analysis was conducted. Results Overall, healthcare professionals viewed the implementation of personalised breast cancer risk estimation as a positive step, but discussion focused on concerns. Three major themes are presented. (1) Service constraints highlights the limited capacity within current breast services and concerns about the impact of additional workload. (2) Risk communication concerns the optimal way to convey risk to women within resource constraints. (3) Accentuating inequity discusses how risk stratification could decrease screening uptake for underserved groups. Conclusions Staff who implemented risk stratification considered it a positive addition to routine screening. They considered it essential to consider improving capacity and demands on healthcare professional time. They highlighted the need for skilled communication of risks and new pathways of care to ensure that stratification could be implemented in financially and time constrained settings without impacting negatively on women.

Tissue fragility, skin hyperextensibility and joint hypermobility are defining characteristics of Ehlers–Danlos syndrome (EDS). Human EDS is subclassified into fourteen types including dermatosparactic EDS, characterized by extreme skin fragility and caused by biallelic ADAMTS2 mutations. We report two novel, ADAMTS2 variants in DNA from EDS-affected dogs. Separate whole-genome sequences from a Pit Bull Terrier and an Alapaha Blue Blood Bulldog each contained a rare, homozygous variant (11:2280117delC, CanFam3.1), predicted to produce a frameshift in the transcript from the first coding ADAMTS2 exon (c.10delC) and a severely truncated protein product, p.(Pro4ArgfsTer175). The clinical features of these dogs and 4 others with the same homozygous deletion included multifocal wounds, atrophic scars, joint hypermobility, narrowed palpebral fissures, skin hyperextensibility, and joint-associated swellings. Due to severe skin fragility, the owners of all 6 dogs elected euthanasia before the dogs reached 13 weeks of age. Cross sections of collagen fibrils in post-mortem dermal tissues from 2 of these dogs showed hieroglyphic-like figures similar to those from cases of severe dermatosparaxis in other species. The whole-genome sequence from an adult Catahoula Leopard Dog contained a homozygous ADAMTS2 missense mutation, [11:2491238G>A; p.(Arg966His)]. This dog exhibited multifocal wounds, atrophic scars, and joint hypermobility, but has survived for at least 9 years. This report expands the spectrum of clinical features of the canine dermatosparactic subtype of EDS and illustrates the potential utility of subclassifying canine EDS by the identity of gene harboring the causal variant.

ImmunoPET is a multicentre, single arm, phase 0-1 study that aims to establish ifThe phase 0 study recruited 5 PD-L1+ patients with metastatic non-small cell lung cancer (NSCLC). Patients received 60MBq/70 kgThis phase 0 study has ethics approval (HREC/65450/PMCC 20/100) and is registered on the Australian Clinical Trials Network (ACTRN12621000171819). The protocol, technical and clinical data will be disseminated by conference presentations and publications. Any modifications to the protocol will be formally documented by administrative letters and must be submitted to the approving HREC for review and approval.Australian Clinical Trials Network ACTRN12621000171819.

Tissue fragility, skin hyperextensibility and joint hypermobility are defining characteristics of Ehlers-Danlos syndrome (EDS). Human EDS is subclassified into fourteen types including dermatosparactic EDS, characterized by extreme skin fragility and caused by biallelic

Background People living with dementia (PLwD) in nursing homes have the right to be safe and to live a life free from harm and abuse; all persons are entitled to this right, regardless of their circumstances or where they live. PLwD are at greater risk of abuse and neglect than those without a diagnosis. Such abuse often goes unnoticed, because dementia may affect a person’s ability to recognise abuse or to report it. In 2021, the Alzheimer Society of Ireland’s Irish Dementia Working Group (IDGW) commissioned the development of a briefing paper to outline the key issues relating to upholding the human rights and safeguarding of PLwD in nursing homes including concrete recommendations for policy and practice. Methods A scoping review of the existing literature on this topic was carried out. This was supplemented by adopting a snowball strategy to identify additional relevant literature. Three co-design online sessions were convened with members of the IDWG in order to discuss and agree on the general content and members also provided suggestions for additional research or policy papers that should be included. Co-design sessions were also used to brainstorm and reach a consensus as a group on recommendations. Results This project identified a number of specific risk factors for PLwD, including organisational abuse, the need to move towards a restraint-free environment, addressing barriers to reporting of abuse and promoting agency and autonomy within safeguarding processes. A number of policy and legislative gaps in our current adult safeguarding framework were identified making it more difficult to adequately protect PLwD in nursing homes. Conclusion 22 recommendations for best practice were developed by the IDWG for nursing home service providers (public and private), health and social care practitioners, policymakers, the Department of Health, HIQA and political representatives in order to collectively advocate for meaningful change.

Alzheimer's disease (AD) is associated with the presence of amyloid plaques in the brain mainly comprised of aggregated forms of amyloid-β (Aβ). Molecules radiolabeled with technetium-99m that cross the blood-brain barrier (BBB) and selectively bind to Aβ plaques have the potential to assist in the diagnosis of AD using single-photon emission computed tomography imaging. In this work, three new tetradentate ligands of pyridyl, amide, amine and thiol donors, featuring a styrylpyridyl group that is known to interact with amyloid plaques, were prepared. The new ligands formed charge-neutral and lipophilic complexes with the [Tc═O]3+ and [Re═O]3+ motifs, and two rhenium complexes were characterized by X-ray crystallography. The rhenium(V) complexes interact with synthetic Aβ1-40 and amyloid plaques on human brain tissue. Two of the new ligands were radiolabeled with 99mTc using a kit-based approach, and their biodistribution in wild-type mice was evaluated. The presence of amide donors in the tetradentate ligand increased the stability of the respective [Tc═O]3+ complexes but reduced brain uptake. While the complexes were able to cross the BBB, the degree of uptake in the brain was not sufficient to justify further investigation of these complexes.

Purpose. There are no currently approved non-invasive methods for detecting tumor treatment responses within the first few days of treatment. The monoclonal antibody, DAB4, or its chimeric derivative, chDAB4 (APOMAB®), targets the Lupus-associated or Sjögren Syndrome-B antigen (La/SSB). La/SSB is over-expressed in malignancy and is selectively targeted by chDAB4 in cancer cells dying after DNA-damaging treatment. Therefore, chDAB4 is a unique diagnostic tool that specifically detects dead cancer cells and could be used to distinguish between chemotherapy responsive and non-responsive patients. In this study, we performed preclinical validation studies using whole-body Positron-Emission Tomography (PET) to examine tumor and normal tissue uptake of 89Zr-labeled chDAB4 in lung or ovarian tumor-bearing mice, which were left untreated or given cisplatin chemotherapy.Methods. The binding of chDAB4 and its conjugates to dead cisplatin-treated human lung and ovarian cancer cells was assessed in vitro as well as its Fc-dependent effector functions. Mice bearing xenografts of H460 lung cancer or A2780 ovarian cancer cells were untreated or given cisplatin chemotherapy followed 24 hours later by 89Zr-labeled chDAB4. Post-cisplatin tumor responses were monitored using bioluminescence imaging and caliper measurements and 89Zr-labeled chDAB4 tumor uptake was measured using an Albira SI PET imager and PMOD analysis software. On completion of experiments, organs were dissected and biodistribution of 89Zr-labeled chDAB4 was measured using a Hidex gamma-counter.Results. The chDAB4 antibody bound only to dead A2780 and H460 cells, and its binding increased with cisplatin treatment in vitro. The chDAB4 antibody did not exhibit Fc-dependent effector functions. Chemotherapy significantly increased uptake of 89Zr-labeled chDAB4 in tumors but not in normal tissues for each tumor model. The greatest differences in average uptake of 89Zr-labeled chDAB4 in subcutaneous tumors were observed 3 days post-cisplatin chemotherapy compared to untreated mice, and before tumor shrinkage was evident.Conclusion. After administration of cisplatin chemotherapy, tumor xenograft uptake of 89Zr-labeled chDAB4 was detected in vivo by PET imaging. Given that the chDAB4 mAb lacked effector activity and that malignant rather than normal tissues were targeted after chemotherapy, these results support clinical development of chDAB4 as both a predictive marker of chemotherapy response and a theranostic imaging agent, which may guide subsequent delivery of chDAB4-directed antibody drug or radio-conjugate anticancer therapies.

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