Healthcare professionals' preferences for surgery or primary endocrine therapy to treat older women with operable breast cancer

Introduction : Primary endocrine therapy (PET) is an alternative treatment to surgery for oestrogen receptor (ER) positive operable breast cancer in older women. However, there is variable use of PET in the UK, with up to 40% of patients aged over 70 receiving PET instead of surgery in some regions. Treatment options offered to patients rely heavily on healthcare professional (HCP) assessment and opinion on which treatments are appropriate. Materials and methods : This was a mixed methods study combining semi-structured interviews with HCPs working in high and low PET regions in the UK, followed by a postal questionnaire survey distributed via the Association of Breast Surgery (ABS). Results : Thirty-four HCPs (20 breast surgeons; 13 nurse specialists; 1 geriatrician) were interviewed from 14 sites across the UK and 252/641 questionnaires returned (39%). There was an overriding view that PET is not suitable for patients under the age of 80 unless there are significant comorbidities. Opinion was split regarding the best way to treat patients with dementia. Patient preference was generally stated to be the most important factor when considering treatment, however only around a quarter 65/244 (26.6%) felt that all patients over the age of 70 should be offered PET as an alternative treatment option. Conclusions : Opinions differ on the best way to treat women over 70 with operable breast cancer, especially if they have co-existing dementia, as well as whether they should be offered PET as a treatment option. This may be a significant cause of treatment variation in the UK. Keywords : Breast cancer; Primary endocrine therapy; Surgery; Elderly; Older; Mixed methods.</p

A Platform for Gastric Cancer Screening in Low- and Middle-Income Countries

Gastric cancer is the second leading cause of cancer death worldwide and screening programs have had a significant impact on reducing mortality. The majority of cases occur in low- and middle-income countries (LMIC), where endoscopy resources are traditionally limited. In this paper, we introduce a platform designed to enable inexpensive gastric screening to take place in remote areas of LMIC. The system consists of a swallowable endoscopic capsule connected to an external water distribution system by a multichannel soft tether. Pressurized water is ejected from the capsule to orient the view of the endoscopic camera. After completion of a cancer screening procedure, the outer shell of the capsule and the soft tether can be disposed, while the endoscopic camera is reclaimed without needing further reprocessing. The capsule, measuring 12 mm in diameter and 28 mm in length, is able to visualize the inside of the gastric cavity by combining waterjet actuation and the adjustment of the tether length. Experimental assessment was accomplished through a set of bench trials, ex vivo analysis, and in vivo feasibility validation. During the ex vivo trials, the platform was able to visualize the main landmarks that are typically observed during a gastric cancer screening procedure in less than 8 min. Given the compact footprint, the minimal cost of the disposable parts, and the possibility of running on relatively available and inexpensive resources, the proposed platform can potentially widen gastric cancer screening programs in LMIC

Detection of anti-drug antibodies using a bridging ELISA compared with radioimmunoassay in adalimumab-treated rheumatoid arthritis patients with random drug levels

Objective: To determine the concordance between RIA and bridging ELISA at detecting anti-drug antibodies (ADAbs) in the context of random adalimumab levels and investigate the additional clinical utility of detecting ADAbs in RA patients who test ADAb positive by RIA and negative by ELISA. Methods: ADAb levels were determined using RIA and bridging ELISA in 63 adalimumab treated RA patients (159 samples). Immunogenicity concordance was determined using receiver-operating characteristic (ROC) curves. To determine the additional clinical value provided by a positive RIA in the presence of negative ELISA, association between treatment response (ΔDAS28), adalimumab drug levels and ADAbs was evaluated longitudinally using generalised estimating equation. Results: Of the 60 RIA+ samples (n=31 patients), 19 (n=10 patients) were also ELISA+, corresponding to 31.7% of samples. Area under the curve (AUC) for detecting ADAbs using ELISA (compared with RIA) using ROC curves was 0.65 (95% CI: 0.59-0.71); this increased to 0.91 (95% CI: 0.81-0.99) if ADAbs were ≥100 AU/ml using RIA. In RIA+/ELISA- patients, adalimumab levels were associated with ΔDAS28 over 12 months [regression coefficient: 0.098 (0.043-0.15), p<0.0001] and whilst ADAbs were significantly associated with drug level, they were not directly associated with ΔDAS28 over 12 months [β coefficient: 0.00083 (-0.0038 to 0.0054), p=0.72]. Conclusion: ADAbs were detected using ELISA more frequently when present in high titres as measured by RIA. In RIA+/ELISA- patients, only drug levels were significantly associated with treatment response. Although ADAbs were not independently associated with treatment response, they may be helpful in determining the aetiology of low drug levels

Seabird diving behaviour reveals the functional significance of shelf-sea fronts as foraging hotspots

This is the author accepted manuscript. The final version is available from the publisher via the DOI in this record.Oceanic fronts are key habitats for a diverse range of marine predators, yet how they influence fine-scale foraging behaviour is poorly understood. Here, we investigated the dive behaviour of northern gannets Morus bassanus in relation to shelf-sea fronts. We GPS tracked 53 breeding birds and examined the relationship between 1901 foraging dives (from time-depth recorders) and thermal fronts (identified via Earth Observation composite front mapping) in the Celtic Sea, North-East Atlantic. We (1) used a habitat use-availability analysis to determine whether gannets preferentially dived at fronts, and (2) compared dive characteristics in relation to fronts to investigate the functional significance of these oceanographic features. We found that relationships between gannet dive probabilities and fronts varied by frontal metric and sex. Whilst both sexes were more likely to dive in the presence of seasonally persistent fronts, links to more ephemeral features were less clear. Here, males were positively correlated with distance to front and cross-front gradient strength, with the reverse for females. Both sexes performed two dive strategies: shallow V-shaped plunge dives with little or no active swim phase (92% of dives), and deeper U-shaped dives with an active pursuit phase of at least three seconds (8% of dives). When foraging around fronts, gannets were half as likely to engage in U-shaped dives compared with V-shaped dives, independent of sex. Moreover, V-shaped dive durations were significantly shortened around fronts. These behavioural responses support the assertion that fronts are important foraging habitats for marine predators, and suggest a possible mechanistic link between the two in terms of dive behaviour. This research also emphasises the importance of cross-disciplinary research when attempting to understand marine ecosystems.This work was funded by a PhD studentship to SLC by the Natural Environment Research Council (NERC; NE/J500380/1), Natural Resources Wales (Seabirds Cymru) and a NERC grant (NE/H007466/1)

Effectiveness and reach of a directed-population approach to improving dental health and reducing inequalities: a cross sectional study

Background Childsmile School adopts a directed-population approach to target fluoride varnish applications to 20% of the primary one (P1) population in priority schools selected on the basis of the proportion of enrolled children considered to be at increased-risk of developing dental caries. The study sought to compare the effectiveness of four different methods for identifying individuals most in need when a directed-population approach is taken. &lt;p&gt;&lt;/p&gt; Methods The 2008 Basic National Dental Inspection Programme (BNDIP) cross-sectional P1 Scottish epidemiological survey dataset was used to model four methods and test three definitions of increased-risk. Effectiveness was determined by the positive predictive value (PPV) and explored in relation to 1-sensitivity and 1-specificity. &lt;p&gt;&lt;/p&gt; Results Complete data was available on 43470 children (87% of the survey). At the Scotland level, at least half (50%) of the children targeted were at increased-risk irrespective of the method used to target or the definition of increased-risk. There was no one method across all definitions of &lt;i&gt;increased-risk&lt;/i&gt; that maximised PPV. Instead, PPV was highest when the targeting method complimented the definition of &lt;i&gt;increased-risk&lt;/i&gt;. There was a higher percentage of children at &lt;i&gt;increased-risk&lt;/i&gt; who were not targeted (1-sensitivity) when caries experience (rather than deprivation) was used to define &lt;i&gt;increased-risk&lt;/i&gt;, irrespective of the method used for targeting. Over all three definitions of &lt;i&gt;increased-risk&lt;/i&gt;, there was no one method that minimised (1-sensitivity) although this was lowest when the method and definition of &lt;i&gt;increased-risk&lt;/i&gt; were complimentary. The false positive rate (1-specificity) for all methods and all definitions of &lt;i&gt;increased-risk&lt;/i&gt; was consistently low (&#60;20%), again being lowest when the method and definition of &lt;i&gt;increased-risk&lt;/i&gt; were complimentary. &lt;p&gt;&lt;/p&gt; Conclusion Developing a method to reach all (or even the vast majority) of individuals at &lt;i&gt;increased-risk&lt;/i&gt; defined by either caries experience or deprivation is difficult using a directed-population approach at a group level. There is a need for a wider debate between politicians and public health experts to decide how best to reach those most at need of intervention to improve health and reduce inequalities. &lt;p&gt;&lt;/p&gt

A proteomics study of rheumatoid arthritis patients on etanercept identifies putative biomarkers associated with clinical outcome measures

\ua9 The Author(s) 2023. Objectives: Biologic DMARDs (bDMARDs) are widely used in patients with RA, but response to bDMARDs is heterogeneous. The objective of this work was to identify pretreatment proteomic biomarkers associated with RA clinical outcome measures in patients starting bDMARDs. Methods: Sequential window acquisition of all theoretical fragment ion spectra mass spectrometry (SWATH-MS) was used to generate spectral maps of sera from patients with RA before and after 3 months of treatment with the bDMARD etanercept. Protein levels were regressed against RA clinical outcome measures, i.e. 28-joint DAS (DAS28) and its subcomponents and DAS28 &lt;2.6 (i.e. remission). The proteins with the strongest evidence for association were analysed in an independent, replication dataset. Finally, subnetwork analysis was carried out using the Disease Module Detection algorithm and biological plausibility of identified proteins was assessed by enrichment analysis. Results: A total of 180 patients with RA were included in the discovery dataset and 58 in the validation dataset from a UK-based prospective multicentre study. Ten individual proteins were found to be significantly associated with RA clinical outcome measures. The association of T-complex protein 1 subunit g with DAS28 remission was replicated in an independent cohort. Subnetwork analysis of the 10 proteins from the regression analysis identified the ontological theme, with the strongest associations being with acute phase and acute inflammatory responses. Conclusion: This longitudinal study of 180 patients with RA commencing etanercept has identified several putative protein biomarkers of treatment response to this drug, one of which was replicated in an independent cohort

Differential Methylation as a Biomarker of Response to Etanercept in Patients With Rheumatoid Arthritis

Objective: Biologic drug therapies represent a huge advance in the treatment of rheumatoid arthritis (RA). However, very good disease control is achieved in only 30% of patients, making identification of biomarkers of response a research priority. We undertook this study to test our hypothesis that differential DNA methylation patterns may provide biomarkers predictive of response to tumor necrosis factor inhibitor (TNFi) therapy in patients with RA. Methods: An epigenome-wide association study was performed on pretreatment whole blood DNA from patients with RA. Patients who displayed good response (n = 36) or no response (n = 36) to etanercept therapy at 3 months were selected. Differentially methylated positions were identified using linear regression. Variance of methylation at differentially methylated positions was assessed for correlation with cis-acting single-nucleotide polymorphisms (SNPs). A replication experiment for prioritized SNPs was performed in an independent cohort of 1,204 RA patients. Results: Five positions that were differentially methylated between responder groups were identified, with a false discovery rate of <5%. The top 2 differentially methylated positions mapped to exon 7 of the LRPAP1 gene on chromosome 4 (cg04857395, P = 1.39 × 10−8 and cg26401028, P = 1.69 × 10−8). The A allele of the SNP rs3468 was correlated with higher levels of methylation for both of the top 2 differentially methylated positions (P = 2.63 × 10−7 and P = 1.05 × 10−6, respectively). Furthermore, the A allele of rs3468 was correlated with European League Against Rheumatism nonresponse in the discovery cohort (P = 0.03; n = 56) and in the independent replication cohort (P = 0.003; n = 1,204). Conclusion: We identify DNA methylation as a potential biomarker of response to TNFi therapy, and we report the association between response and the LRPAP1 gene, which encodes a chaperone of low-density lipoprotein receptor–related protein 1. Additional replication experiments in independent sample collections are now needed

Concealed concern: Fathers' experience of having a child with Juvenile Idiopathic Arthritis

Despite increased research into families of chronically ill children, more needs to be known about the father’s experience. We address this issue through asking: ‘What is it like to be the father of a child with juvenile idiopathic arthritis?’ (JIA). Four members of eight families with an adolescent diagnosed with JIA, including seven fathers, were interviewed and transcripts analyzed using grounded theory. This study suggests that fathers of children with JIA experience several severe losses which are exacerbated through comparisons they make between their own situation and that of fathers of healthy children. In addition, the fathers faced several constraints which reduced their opportunities to communicate with their ill child through shared activities. Fathers appeared to conceal their distress by adopting strategies of denial and distraction however their adjustment was facilitated, to some extent, by social support. They could also develop greater acceptance of their situation over time as the care of their ill child became assimilated into family life and constraints upon their life gradually reduced through the increased maturity of their son or daughter with JIA. These findings have implications for healthcare professionals and voluntary organizations

A survey of owners' perceptions of fear of fireworks in a sample of dogs and cats in New Zealand

AIMS: To establish reliable information regarding the behavioural responses of dogs and cats to fireworks in New Zealand; record interventions used by owners, and their perceived efficacies; and establish the prevalence of firework-related injury, and quantify owners' attitudes towards fireworks. METHODS: A questionnaire targeting dog and cat owners was distributed via the Auckland Society for the Prevention of Cruelty to Animals (SPCA) Animals Voice magazine and 25 veterinary clinics. The questionnaire covered demographics of animals, fear of fireworks, severity of the fear, and behaviours exhibited. Also included were treatments tried, source and perceived efficacy, prevalence of injury, and owners' attitudes towards the sale of fireworks for private use. RESULTS: From a total of 8,966 questionnaires distributed, 1,007 valid questionnaires were returned, representing 3,527 animals. Of these 1,635 (46%) animals displayed a level of fear of fireworks recognisable to their owners. Owners of dogs identified a significantly higher fear response than owners of cats but the duration of these fear responses did not differ between species. Fear of fireworks frequently resulted in dogs exhibiting active fear behaviours, whereas cats were more likely to exhibit hiding and cowering behaviours. A significantly increased severity and duration of fear response over time in dogs and cats was associated with owners who comforted them when they displayed a fearful response. Only 141/890 (15.8%) of owners sought professional treatment from a veterinarian, animal behaviourist or animal trainer for their animals, with variable efficacy. Six percent (51/923) of animals had received physical injuries from fireworks. The majority (837/1,007; 83%) of respondents, regardless of whether they owned a fearful animal or not, supported a ban on the sale of fireworks for private use. CONCLUSIONS: The results provide valuable information that is, as yet, unsubstantiated in New Zealand, although potential biases exist due to the non-random selection of respondents. Differences between dogs and cats were likely due to differing responses to fear-provoking stimuli between the species. Owner-reported increase in fearful response over time for comforted animals may indicate a negative impact on the longer-term psychological welfare of their animal. CLINICAL RELEVANCE: The greater the awareness of effective treatment plans for animals that suffer from a fear of fireworks, the greater the possibility that this fear can be reduced. Wider dissemination of effective owner behaviour and treatment programmes for firework fears is needed to improve levels of professional treatment for dogs and cats

Biology of primary breast cancer in older women treated by surgery: with correlation with long-term clinical outcome and comparison with their younger counterparts

BACKGROUND: As age advances breast cancer appears to change its biological characteristics, however, very limited data are available to define the precise differences between older and younger patients. METHODS: Over 36 years (1973–2009), 1758 older (⩾70 years) women with early operable primary breast cancer were managed in a dedicated clinic. In all, 813 underwent primary surgery and 575 good quality tumour samples were available for biological analysis. The pattern of biomarkers was analysed using indirect immunohistochemistry on tissue microarrays. Comparison was made with a previously characterised series of younger (<70 years) patients. RESULTS: There was high expression of oestrogen receptor (ER), PgR, Bcl2, Muc1, BRCA1 and 2, E-cadherin, luminal cytokeratins, HER3, HER4, MDM2 and 4 and low expression of human epidermal growth factor receptor (HER)-2, Ki67, p53, EGFR and CK17. Oestrogen receptor and axillary stage appeared as independent prognostic factors. Unsupervised partitional clustering showed six biological clusters in older patients, five of which were common in the younger patients, whereas the low ER luminal cluster was distinct in the older series. The luminal phenotype showed better breast cancer-specific survival, whereas basal and HER2-overexpressing tumours were associated with poor outcome. CONCLUSION: Early operable primary breast cancer in older women appears as a distinct biological entity, with existence of a novel cluster. Overall older women showed less aggressive tumour biology and ER appeared as an independent prognostic factor alongside the time-dependent axillary stage. These biological characteristics may explain the differences in clinical outcome and should be considered in making therapeutic decisions