Particles and Waves: Poetic Responses to Place - Psycho-geography and/as practice

Utilising a range of psychogeographic practices, this project comprises a hybrid creative response to the natural landscape of West Wales, using the River Towy as a focal point. It is concerned with an exploration of the importance of identity, and with themes of the spiritual, land, gender, culture and history. The work’s originality results from the application of predominantly male urban writing practices in a rural Welsh environment from a woman’s standpoint. The journey recounted in the creative piece is understood essentially as a transformative, personal process of a transcendental nature, whilst also exploring and depicting the nature of the differing stages of the river and those who live in or come to the specific locations, including Carmarthen, the Cambrian Mountains, Llandeilo, Llandovery, and Llansteffan. It is informed by the belief that some places are imbued with energies that may cause specific types of human interaction and responses. The project was developed through investigative visits to predetermined sites at significant positions and with notable histories, in order to ascertain and record what might be felt, observed and experienced, leading to site-specific writing. It is formally diverse, including short essays, prose and poetry of various kinds, the use of found texts. It is presented as a ‘scrapbook’ and makes creative use of the interplay between text and image. The multi-layered approach assumes that myths, fiction and fact are all of equal importance and intuitive skills are acknowledged as essential. The work, thus, is informed by recent developments in psychogeography, i.e. ‘mythogeography’ or ‘deep topography’. The writing is experimental and influenced by the zeitgeist preference for abbreviated/truncated writing. The methodologies of this practice-based project include autoethnographic responses and an exploration of psychogeographic literature and practice. The creative piece is supported by a wide and deep contextual background, which has informed its development

The prescription and monitoring of conventional synthetic disease-modifying anti-rheumatic drugs: British Society for Rheumatology guideline scope

Lay Summary: What does this mean for patients? A revised guideline, produced by the British Society for Rheumatology (BSR), will provide up-to-date information about the safe prescribing and monitoring of the effects of non-biologic (or conventional synthetic) disease-modifying anti-rheumatic drugs (DMARDs). This guideline will be used by healthcare professionals, people living with autoimmune rheumatic diseases and other interested parties, such as patient groups and charities. DMARDs are a group of drugs prescribed to people with autoimmune rheumatic diseases. The main aims of these drugs are to control symptoms and reduce or prevent long-term progression of the disease. Biologic drugs and Janus kinase inhibitors—sometimes referred to as biologic DMARDs and targeted synthetic DMARDs, respectively—are excluded from this guideline. This article outlines the scope of the revised guideline for DMARD safety, which will be updated to include new information and is being extended to include children and young people. Guideline revisions will be undertaken by a working group of adult and paediatric and adolescent rheumatologists, other healthcare professionals and people living with autoimmune rheumatic disease. The guideline will be developed using the methods and processes outlined in the BSR document ‘Creating clinical guidelines: our protocol’

Therapeutic options for mucinous ovarian carcinoma

OBJECTIVE: Mucinous ovarian carcinoma (MOC) is an uncommon ovarian cancer histotype that responds poorly to conventional chemotherapy regimens. Although long overall survival outcomes can occur with early detection and optimal surgical resection, recurrent and advanced disease are associated with extremely poor survival. There are no current guidelines specifically for the systemic management of recurrent MOC. We analyzed data from a large cohort of women with MOC to evaluate the potential for clinical utility from a range of systemic agents. METHODS: We analyzed gene copy number (n = 191) and DNA sequencing data (n = 184) from primary MOC to evaluate signatures of mismatch repair deficiency and homologous recombination deficiency, and other genetic events. Immunohistochemistry data were collated for ER, CK7, CK20, CDX2, HER2, PAX8 and p16 (n = 117-166). RESULTS: Molecular aberrations noted in MOC that suggest a match with current targeted therapies include amplification of ERBB2 (26.7%) and BRAF mutation (9%). Observed genetic events that suggest potential efficacy for agents currently in clinical trials include: KRAS/NRAS mutations (66%), TP53 missense mutation (49%), RNF43 mutation (11%), ARID1A mutation (10%), and PIK3CA/PTEN mutation (9%). Therapies exploiting homologous recombination deficiency (HRD) may not be effective in MOC, as only 1/191 had a high HRD score. Mismatch repair deficiency was similarly rare (1/184). CONCLUSIONS: Although genetically diverse, MOC has several potential therapeutic targets. Importantly, the lack of response to platinum-based therapy observed clinically corresponds to the lack of a genomic signature associated with HRD, and MOC are thus also unlikely to respond to PARP inhibition

The prescription and monitoring of conventional synthetic disease-modifying anti-rheumatic drugs:British Society for Rheumatology guideline scope

This guideline will provide up-to-date, evidence-based recommendations on the safe use of non-biologic DMARDs, also called conventional synthetic DMARDs (csDMARD), across the full spectrum of autoimmune rheumatic diseases. The guideline will update the guideline published in 2017 and will be expanded to include people of all ages. Updated information on the monitoring of DMARDs and vaccinations will be included. The guideline will be developed using the methods and processes described in the British Society for Rheumatology’s ‘Creating clinical guidelines: our protocol’, updated 2023

Holistic health and social care outreach for people experiencing homelessness with recent non-fatal overdose in Glasgow, Scotland: the Pharmacist and third sector Homeless charity worker Outreach Engagement Non-medical Independent prescriber Rx (PHOENIx) pilot randomised controlled trial

Objectives: To examine randomised controlled trial (RCT) progression criteria including emergency department (ED) attendance and non-fatal overdose, from a holistic, integrated health and social care outreach intervention (PHOENIx), for people experiencing homelessness with recent non-fatal street drug overdose. Design: Pilot RCT. 1:1 randomisation to PHOENIx plus usual care (UC) or UC. Setting: Glasgow, Scotland. Participants: 128 adults experiencing homelessness with at least one non-fatal street drug overdose in the preceding 6 months. Interventions: Pharmacists from the National Health Service and third sector homelessness workers offered weekly outreach. PHOENIx teams develop therapeutic relationships to address health (physical health, mental health and problem drug use) and social care (housing, welfare benefits and social prescribing) in addition to UC. UC comprised building-based primary and secondary health, social and third sector services. Outcomes: Primary: progression criteria: recruitment (≥100 participants in 4 months); ≥80% of participants with data collected at baseline, 6 and 9 months; ≥60% of participants retained in the trial at each follow-up period (6 and 9 months); ≥60% of participants receiving the intervention weekly; any reduction in the rate of presentation to ED and overdoses, at 6- or 9-month follow-up. Secondary: participants with, and time to: hospitalisations; health-related quality of life (QoL); treatment uptake for physical and mental health conditions, and problematic drug use. Results: Progression criteria were exceeded. In PHOENIx compared with UC, there appeared to be a delay in the median time to ED visit, overdose and hospitalisation but no improvement in number of participants with ED visits, overdoses or hospitalisations. QoL and treatment uptake appeared to be higher in PHOENIx versus UC at 6 and 9 months. Conclusions: A definitive RCT is merited, to assess the impact of PHOENIx on people with multiple, severe disadvantages

Development and validation of a targeted gene sequencing panel for application to disparate cancers

Next generation sequencing has revolutionised genomic studies of cancer, having facilitated the development of precision oncology treatments based on a tumour’s molecular profile. We aimed to develop a targeted gene sequencing panel for application to disparate cancer types with particular focus on tumours of the head and neck, plus test for utility in liquid biopsy. The final panel designed through Roche/Nimblegen combined 451 cancer-associated genes (2.01 Mb target region). 136 patient DNA samples were collected for performance and application testing. Panel sensitivity and precision were measured using well-characterised DNA controls (n = 47), and specificity by Sanger sequencing of the Aryl Hydrocarbon Receptor Interacting Protein (AIP) gene in 89 patients. Assessment of liquid biopsy application employed a pool of synthetic circulating tumour DNA (ctDNA). Library preparation and sequencing were conducted on Illumina-based platforms prior to analysis with our accredited (ISO15189) bioinformatics pipeline. We achieved a mean coverage of 395x, with sensitivity and specificity of >99% and precision of >97%. Liquid biopsy revealed detection to 1.25% variant allele frequency. Application to head and neck tumours/cancers resulted in detection of mutations aligned to published databases. In conclusion, we have developed an analytically-validated panel for application to cancers of disparate types with utility in liquid biopsy

Constraints on the χ_(c1) versus χ_(c2) polarizations in proton-proton collisions at √s = 8 TeV

The polarizations of promptly produced χ_(c1) and χ_(c2) mesons are studied using data collected by the CMS experiment at the LHC, in proton-proton collisions at √s=8  TeV. The χ_c states are reconstructed via their radiative decays χ_c → J/ψγ, with the photons being measured through conversions to e⁺e⁻, which allows the two states to be well resolved. The polarizations are measured in the helicity frame, through the analysis of the χ_(c2) to χ_(c1) yield ratio as a function of the polar or azimuthal angle of the positive muon emitted in the J/ψ → μ⁺μ⁻ decay, in three bins of J/ψ transverse momentum. While no differences are seen between the two states in terms of azimuthal decay angle distributions, they are observed to have significantly different polar anisotropies. The measurement favors a scenario where at least one of the two states is strongly polarized along the helicity quantization axis, in agreement with nonrelativistic quantum chromodynamics predictions. This is the first measurement of significantly polarized quarkonia produced at high transverse momentum

Autism spectrum disorder and food neophobia: clinical and subclinical links

Background: Autism spectrum disorder (ASD) has been linked with eating and feeding related atypicalities , including food neophobia (refusal to try unfamiliar foods) , since its earliest description. Nevertheless, whether associations between ASD traits and food neophobia extend subclinical ly into t he broader population of children and their potential additive health impacts remain unexplored . Objective: We examine d ASD - control group differences in food neophobia and ASD trait - food neophobia trait associations as well as the ability of food neophobia and autistic traits to predict one index of later health - related outcomes (body mass index) . D es ign : Participants in the present study were a large commun ity - based sample of 8 - 11 year old s (n=4,564 ) , including a relatively small group o f children diagnosed with ASD (n =37) . Parents of these 8 - 11 - year - old children completed assessments of food neophobia and autistic traits, as well as providing height and weight metrics at 12 years of age . Results: C hildren with ASD were rated as more food neophobic than their same - age non - ASD peers ( 2.67+/ - 0.83 vs. 2.22 +/ - 0.73; p <.001) and there were subclinical associations between food neophobia and ASD traits (all three of social, communication, and restricted/repetitive behavior) in th is community - based sample of children ( p s<.05) . Moreover, while food neophobia alone predicted lower body mass index, the interaction of food neophobia and ASD traits predicted higher body mass index ( p s < .01) , suggesting that elevated ASD traits in combination with food neophobia exert opposing influences on weight to food neophobia alone . Conclusions: These findings implicate clinical and subclinical connections between ASD traits and feeding behaviors that could impact health outcomes and therefore should be further explored in future studies of shared etiology and intervention strategy

Homologous recombination DNA repair defects in PALB2- associated breast cancers

Abstract: Mono-allelic germline pathogenic variants in the Partner And Localizer of BRCA2 (PALB2) gene predispose to a high-risk of breast cancer development, consistent with the role of PALB2 in homologous recombination (HR) DNA repair. Here, we sought to define the repertoire of somatic genetic alterations in PALB2-associated breast cancers (BCs), and whether PALB2-associated BCs display bi-allelic inactivation of PALB2 and/or genomic features of HR-deficiency (HRD). Twenty-four breast cancer patients with pathogenic PALB2 germline mutations were analyzed by whole-exome sequencing (WES, n = 16) or targeted capture massively parallel sequencing (410 cancer genes, n = 8). Somatic genetic alterations, loss of heterozygosity (LOH) of the PALB2 wild-type allele, large-scale state transitions (LSTs) and mutational signatures were defined. PALB2-associated BCs were found to be heterogeneous at the genetic level, with PIK3CA (29%), PALB2 (21%), TP53 (21%), and NOTCH3 (17%) being the genes most frequently affected by somatic mutations. Bi-allelic PALB2 inactivation was found in 16 of the 24 cases (67%), either through LOH (n = 11) or second somatic mutations (n = 5) of the wild-type allele. High LST scores were found in all 12 PALB2-associated BCs with bi-allelic PALB2 inactivation sequenced by WES, of which eight displayed the HRD-related mutational signature 3. In addition, bi-allelic inactivation of PALB2 was significantly associated with high LST scores. Our findings suggest that the identification of bi-allelic PALB2 inactivation in PALB2-associated BCs is required for the personalization of HR-directed therapies, such as platinum salts and/or PARP inhibitors, as the vast majority of PALB2-associated BCs without PALB2 bi-allelic inactivation lack genomic features of HRD