Abstract Background Pharmacogenomics (PGx) uses genetic information to personalize medication, reducing adverse reactions and improving efficacy. Despite its promise, low public awareness and disparities in PGx acceptability among under-represented groups may exacerbate health inequalities. The objective of this study was to elucidate a British South Asian community’s attitudes toward personalised prescribing. Methods Adults of Bangladeshi or Pakistani ancestry from the Genes & Health (G&H) study completed a survey. Community feedback guided theme prioritization. Multivariable logistic regression analyses (controlling for age and gender) explored relationships among survey variables, and case–control Genome Wide Association Studies (GWAS) and candidate variant enrichment analysis examined the genetic architecture underlying herbal remedy use. Results Out of 553 respondents (57% female, mostly aged 25–54), 72% reported medication inefficacy, and 54% experienced side effects. Herbal remedies were widely used (66%), notably Black seed (39%), Turmeric (37%), and Ginger (36%). Participants who reported not using traditional or herbal medicines had higher medication adherence MARS-5 scores (Odds Ratio (OR) 1.10, 95% Confidence Interval (CI) 1.05–1.16, p < 0.0002). All three commonly used herbal remedies inhibit the pharmacogenomically variable CYP2C9 enzyme responsible for metabolising commonly used medications. 58% of respondents were willing to provide DNA samples for PGx testing, yet 70% agreed that they would be more likely to take medication as instructed if PGx results suggested the medicine would suit them. Concerns about PGx testing were common (27%), especially among non-English speakers. Most (69%) were concerned about misuse of PGx data, particularly by pharmaceutical companies (82%). Importantly, 87% demanded stronger PGx data protections compared to other health data. Conclusions Compared to a national UK population, the surveyed subpopulation reported higher rates of adverse drug reactions (ADRs) and perceived medication inefficacy, yet fewer respondents indicated willingness to undergo PGx testing. This highlights the need for tailored implementation strategies and underscores the importance of engaging underrepresented populations in policy development. The inverse relationship between medication adherence and herbal remedy use indicates an association between cultural health practices and medication behaviours that merits further investigation. Increased awareness of the common use of these CYP2C9 inhibitors and further research into the genetic architecture underlying herbal remedy use are warranted.

BackgroundDespite the broad availability of antihypertensive drugs, approximately 40% of hypertensive patients fail to achieve the recommended blood pressure (BP) levels and may require alternative treatment(s). At present, renal denervation is the only proven non-pharmacological device-based alternative treatment available, but it is a costly, invasive, hospital-based procedure that is unlikely to be widely available. Transcutaneous autonomic neuromodulation (tAN)—if shown to be safe, acceptable, and efficacious—can offer a non-invasive, inexpensive, self-administered device-based innovative adjunct or alternative to pharmacological therapy.MethodsSCRATCH-HTN is a double-blind, sham-controlled trial, with 63 participants randomised on a 2:1 basis to receive either tAN or sham-tAN treatment. Hypertensive patients on medication were included if they had elevated systo-diastolic BPs on daytime ambulatory BP monitoring (ABPM) [systolic BP (SBP) of ≥135 and <170 mmHg and mean daytime diastolic BP (DBP) of ≥85 and <115 mmHg]. Participants were trained to self-administer tAN therapy for 30 min every day for first 14 days and then once a week for 10 weeks. The primary endpoint was change in daytime ambulatory SBP from baseline to 3 months. Secondary endpoints included change in 24-h ambulatory and office SBP and DBP, BP variability, heart rate variability, quality of life, and sleep quality from baseline to end of treatment. Other exploratory outcomes included evaluation of impact on functional exercise (6-min walk test), structural and functional changes in the heart, cognitive function, and central blood pressures. A subgroup of patients underwent detailed autonomic functional assessment at the start and end of the study.ConclusionThe SCRATCH-HTN trial is a phase 2a study testing the safety, acceptability, and potential efficacy of tAN treatment for improving blood pressure control in patients with elevated BP despite medication. It also explores the effects of tAN on sleep, exercise tolerance, heart rate variability, central BP, cardiac structure, and autonomic function. If effective, it could offer a transformative approach to hypertension management. Study Protocol RegistrationClinicaltrials.gov, identifier NCT05179343 and ISRCTN (14509154).

Background:Biochemical urine analysis by liquid chromatography-mass spectrometry analysis (ie, chemical adherence testing [CAT]) is an objective method of detecting non-adherence to antihypertensive treatment. We aimed to assess whether an intervention based on providing non-adherent patients with hypertension with information on their urine analysis results combined with a discussion of the main reasons for non-adherence (CAT-guided intervention) would lead to a cost-effective improvement in adherence, blood pressure, and urinary excretion of albumin. Methods:OUTREACH was a multicentre, randomised controlled trial in 12 UK secondary or tertiary outpatient centres and primary care services. We recruited non-pregnant patients with hypertension who were older than 18 years and were on at least two antihypertensive medications. Participants who were non-adherent to antihypertensive treatment based on the results of their first urine CAT were randomly assigned (1:1) either to the intervention (discussion of the results of the urine CAT; group A) or standard of care (group B) after visit 2. The sequence of randomisation was computer-generated through an automated randomisation service (Sealed Envelope), which used minimisation as a method of allocation based on recruitment site, baseline systolic blood pressure, age, sex, number of antihypertensive medications prescribed at visit 1, the improvement in biochemical adherence to antihypertensive treatment between visits 1 and 2, and a random element to ensure the unpredictability of the assignment. The primary outcome was the mean clinic systolic blood pressure measured at visit 4. All analyses were based on the intention-to-treat principle. The trial was registered with ClinicalTrials.gov (NCT03293147) and is completed. Findings:Between Feb 4, 2019, and Feb 1, 2023, 879 patients were assessed for eligibility, 748 of whom were excluded after visit 1; 720 because they were either adherent or had unconfirmed adherence status on urine CAT. 70 adherent individuals were retained on the study for masking purposes but were not a part of the two-arm randomised component of the study. 130 non-adherent patients included in the study were randomly assigned to the intervention group (A; n=65) or the standard of care group (B; n=65). 71 (55%) participants were male and 59 (45%) were female; 57 (44%) were White, 22 (17%) were Asian or Asian British, 49 (38%) were Black, African, Caribbean, or Black British, and two (2%) were other ethnicities. The median follow-up after the intervention to visit 4 was 2·8 months (IQR 2·2-4·3). Mean clinic systolic blood pressure at visit 4 was 150·9 mm Hg (SD 24·7) in 56 participants in group A and 151·1 mm Hg (24·4) in 55 participants in group B (adjusted mean difference -5·1 mm Hg [95% CI -12·7 to 2·5]; p=0·19). 33 adverse events were reported (11 in group A and 22 in group B). 12 serious adverse events were recorded during the trial, occurring in five (8%) of 65 participants in group A and five (8%) of 65 participants in group B (two participants in group B had two serious adverse events each). Interpretation:CAT-guided intervention did not show a significant effect on clinic systolic blood pressure, but the study was underpowered. Larger studies are required to better understand the effect of urine CAT-guided interventions on blood pressure. Funding:British Heart Foundation, National Institute for Health and Care Research Manchester Biomedical Research Centre, Manchester Academic Health Science Centre, and Omron.

Background The objective of the PERSONAL‐CovidBP (Personalised Electronic Record Supported Optimisation When Alone for Patients With Hypertension: Pilot Study for Remote Medical Management of Hypertension During the COVID‐19 Pandemic) trial was to assess the efficacy and safety of smartphone‐enabled remote precision dosing of amlodipine to control blood pressure (BP) in participants with primary hypertension during the COVID‐19 pandemic. Methods and Results This was an open‐label, remote, dose titration trial using daily home self‐monitoring of BP, drug dose, and side effects with linked smartphone app and telemonitoring. Participants aged ≥18 years with uncontrolled hypertension (5–7 day baseline mean ≥135 mm Hg systolic BP or ≥85 mm Hg diastolic BP) received personalized amlodipine dose titration using novel (1, 2, 3, 4, 6, 7, 8, 9 mg) and standard (5 and 10 mg) doses daily over 14 weeks. The primary outcome of the trial was mean change in systolic BP from baseline to end of treatment. A total of 205 participants were enrolled and mean BP fell from 142/87 (systolic BP/diastolic BP) to 131/81 mm Hg (a reduction of 11 (95% CI, 10–12)/7 (95% CI, 6–7) mm Hg, P<0.001). The majority of participants achieved BP control on novel doses (84%); of those participants, 35% were controlled by 1 mg daily. The majority (88%) controlled on novel doses had no peripheral edema. Adherence to BP recording and reported adherence to medication was 84% and 94%, respectively. Patient retention was 96% (196/205). Treatment was well tolerated with no withdrawals from adverse events. Conclusions Personalized dose titration with amlodipine was safe, well tolerated, and efficacious in treating primary hypertension. The majority of participants achieved BP control on novel doses, and with personalization of dose there were no trial discontinuations due to drug intolerance. App‐assisted remote clinician dose titration may better balance BP control and adverse effects and help optimize long‐term care. Registration URL: clinicaltrials.gov. Identifier: NCT04559074.

Background People need high-quality information to make decisions about research participation. Providing information in written format alone is conventional but may not be the most effective and acceptable approach. We developed a structure for the presentation of information using multimedia which included generic and trial-specific content. Our aim was to embed ‘Studies Within A Trial’ (SWATs) across multiple ongoing trials to test whether multimedia presentation of patient information led to better rates of recruitment. Methods Five trials included a SWAT and randomised their participants to receive a multimedia presentation alongside standard information, or standard written information alone. We collected data on trial recruitment, acceptance and retention and analysed the pooled results using random effects meta-analysis, with the primary outcome defined as the proportion of participants randomised following an invitation to take part. Results Five SWATs provided data on the primary outcome of proportion of participants randomised. Multimedia alongside written information results in little or no difference in recruitment rates (pooled odds ratio = 0.96, 95% CI: 0.79 to 1.17, p -value = 0.671, I 2 = 0%). There was no effect on any other outcomes. Conclusions Multimedia alongside written information did not improve trial recruitment rates. Trial registration ISRCTN71952900, ISRCTN 06710391, ISRCTN 17160087, ISRCTN05926847, ISRCTN62869767.

Percutaneous coronary intervention (PCI) is frequently performed for stable angina. However, the first blinded trial, ORBITA, did not show a placebo-controlled increment in exercise time in patients with single-vessel disease, at 6 weeks, on maximal antianginal therapy. ORBITA-2 will assess the placebo-controlled efficacy of PCI on angina frequency in patients with single- or multivessel disease, at 12 weeks, on no antianginal therapy. ORBITA-2 is a double-blind placebo-controlled trial randomising participants with (i) angina at presentation, (ii) documented angina during the 2-week pre-randomisation symptom assessment phase, (iii) objective evidence of ischaemia, (iv) single- or multivessel disease, and (v) clinical eligibility for PCI. At enrolment, antianginals will be stopped, and angina questionnaires completed. Participants will record their symptoms on a smartphone application daily throughout the trial and will undergo exercise treadmill testing and stress echocardiography at pre-randomisation. They will then undergo coronary angiography with unblinded invasive physiology assessment. Eligible participants will then be sedated to a deep level of conscious sedation and randomised 1:1 between PCI and placebo. After the 12-week blinded follow-up period, they will return for questionnaires, exercise testing and stress echocardiography assessment. If angina becomes intolerable, antianginals will be introduced using a prespecified medication protocol. The primary outcome is an angina symptom score using an ordinal clinical outcome scale for angina. Secondary outcomes include exercise treadmill time, angina frequency, angina severity and quality of life. Trial registration: ClinicalTrials.gov: NCT03742050.

Abstract Clinically non-functioning pituitary adenomas (NFPAs) represent the second most common subtype of pituitary tumours, representing 15-43% of all pituitary adenomas. NFPAs are usually benign tumours with no clinical evidence of hormonal hypersecretion. In most of the cases the tumours are arising from the gonadotroph linage, but silent corticotroph, somatotroph, thyrotroph and rarely lactotroph cell characteristics can be discovered with immunostaining. As a result of lack of hormonal hyper-secretion, the diagnosis of NFPAs is made most often when the patient presents with mass effects due to a macroadenoma. NFPAs are most common tumour types in surgical series, and their primary treatment is indeed surgery. However, complete resection is achieved only in about 66% of the cases, and 20% of gross total resected tumours recur after 10 years. Over the past few decades, remarkable progress has been achieved regarding medical treatment options for pituitary tumours. However, NFPAs remain the only subtype with no widely accepted pharmacological treatment. Dopamine receptor type 2 (DRD2) and somatostatin receptor (SST) expression have been demonstrated in NFPAs, prompting the investigation of dopamine agonists and somatostatin analogues as potential treatment strategies. The DRD2 agonist cabergoline is already used as first-line treatment of prolactinomas to induce tumour shrinkage and reduce prolactin secretion. Here we aim to investigate the efficacy of cabergoline on human NFPA tissue. We assessed DRD2 expression levels via immunohistochemistry and qPCR in a large cohort of NFPAs (n=40) and in few prolactinomas (n=10). D2DR has two different isoforms, long (D2RL) and short (D2RS), which are differently expressed and can induce different effects on cell viability. In cabergoline-sensitive prolactinomas D2RS is the predominant isoform. NFPAs shown 10-fold and 5-fold decrease expression of D2RS and D2RL compared to prolactinomas, respectively. Additionally, in NFPAs we observed a significant decrease of cAMP production after cabergoline treatment (45% ±7; p<0.0001); however, viability after one-week cabergoline treatment showed only 4% (±0.7; p<0.0002) reduction, compared to a 10% decrease in prolactinomas (p<0.05). We also observed no difference in secretion of chromogranin A release in NFPAs upon treatment with cabergoline. We have also seen in NFPAs downregulation of Ga i2 protein expression levels, highlighting the general decrease of expression levels in the dopamine pathway (50% less, p<0.004). Our data suggest that the difference in cabergoline responses between NFPAs and prolactinomas may be due to their distinct expression of D2DR isoforms, which differ by 29 amino acids in the third cytoplasmic loop, essential for G-protein binding. It has been shown that D2RL, but not D2RS, requires Gai2. The difference in D2R isoform expression could translate to distinct G-protein activation, ultimately leading to the contrasting viability results after cabergoline treatment. Taken together, these data will help inform future treatment strategies for patients with NFPAs. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

Percutaneous coronary intervention (PCI) is frequently performed for stable angina. However, the first blinded trial, ORBITA, did not show a placebo-controlled increment in exercise time in patients with single-vessel disease, at 6 weeks, on maximal antianginal therapy. ORBITA-2 will assess the placebo-controlled efficacy of PCI on angina frequency in patients with single- or multivessel disease, at 12 weeks, on no antianginal therapy. ORBITA-2 is a double-blind placebo-controlled trial randomising participants with (i) angina at presentation, (ii) documented angina during the 2-week pre-randomisation symptom assessment phase, (iii) objective evidence of ischaemia, (iv) single- or multivessel disease, and (v) clinical eligibility for PCI. At enrolment, antianginals will be stopped, and angina questionnaires completed. Participants will record their symptoms on a smartphone application daily throughout the trial and will undergo exercise treadmill testing and stress echocardiography at pre-randomisation. They will then undergo coronary angiography with unblinded invasive physiology assessment. Eligible participants will then be sedated to a deep level of conscious sedation and randomised 1:1 between PCI and placebo. After the 12-week blinded follow-up period, they will return for questionnaires, exercise testing and stress echocardiography assessment. If angina becomes intolerable, antianginals will be introduced using a prespecified medication protocol. The primary outcome is an angina symptom score using an ordinal clinical outcome scale for angina. Secondary outcomes include exercise treadmill time, angina frequency, angina severity and quality of life. Trial registration: ClinicalTrials.gov: NCT03742050.

Barts NIHR Biomedical Research Centre, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK; Department of Anesthetics, King’s College Hospital NHS Foundation Trust and King’s College School of Medicine and Dentistry, London SE5 9RS, UK; and Department of Physiology, Translational Cardio-Respiratory Laboratory, School of Medical Sciences, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand

BACKGROUND: Barts Health National Health Service Trust (BHNHST) serves a diverse population of 2.5 million people in London, UK. We undertook a health services assessment of factors used to evaluate the risk of severe acute respiratory coronavirus 2 (SARS-CoV-2) infection.METHODS: Patients with confirmed polymerase chain reaction (PCR) test results admitted between 1 March and 1 August 2020 were included, alongwith clinician-diagnosed suspected cases. Prognostic factors from the 4C Mortality score and 4C Deterioration scores were extracted from electronic health records and logistic regression was used to quantify the strength of association with 28-day mortality and clinical deterioration using national death registry linkage.RESULTS: Of 2783 patients, 1621 had a confirmed diagnosis, of whom 61% were male and 54% were from Black and Minority Ethnic groups; 26% died within 28 days of admission. Mortality was strongly associated with older age. The 4C mortality score had good stratification of risk with a calibration slope of 1.14 (95% CI 1.01-1.27). It may have under-estimated mortality risk in those with a high respiratory rate or requiring oxygen.CONCLUSION: Patients in this diverse patient cohort had similar mortality associated with prognostic factors to the 4C score derivation sample, but survival might be poorer in those with respiratory failure.

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

The information given to people considering taking part in a trial needs to be easy to understand if those people are to become, and then remain, trial participants. However, there is a tension between providing comprehensive information and providing information that is comprehensible. User-testing is one method of developing better participant information, and there is evidence that user-tested information is better at informing participants about key issues relating to trials. However, it is not clear if user-testing also leads to changes in the rates of recruitment in trials, compared to standard trial information. As part of a programme of research, we embedded ‘studies within a trial’ (SWATs) across multiple ongoing trials to see if user-tested materials led to better rates of recruitment. Seven ‘host’ trials included a SWAT evaluation and randomised their participants to receive routine information sheets generated by the research teams, or information sheets optimised through user-testing. We collected data on trial recruitment and analysed the results across these trials using random effects meta-analysis, with the primary outcome defined as the proportion of participants randomised in a host trial following an invitation to take part. Six SWATs (n=27,805) provided data on recruitment. Optimised participant information sheets likely result in little or no difference in recruitment rates (7.2% versus 6.8%, pooled odds ratio = 1.03, 95% CI 0.90 to 1.19, p-value = 0.63, I2 = 0%). Participant information sheets developed through user testing did not improve recruitment rates. The programme of work showed that co-ordinated testing of recruitment strategies using SWATs is feasible and can provide both definitive and timely evidence on the effectiveness of recruitment strategies. Healthlines Depression (ISRCTN14172341) Healthlines CVD (ISRCTN27508731) CASPER (ISRCTN02202951) ISDR (ISRCTN87561257) ECLS (NCT01925625) REFORM (ISRCTN68240461) HeLP Diabetes (ISRCTN02123133)

The neural cell adhesion molecule (NCAM) has previously been studied in pituitary neuroendocrine tumours (PitNETs), but its role in tumour biology and aggressiveness remains controversial, and its relationship with the tumour microenvironment remains unknown. We aimed to characterise NCAM expression in PitNETs, to correlate this with clinico-pathological features, and to assess the role of various microenvironment components on NCAM expression. NCAM and immune cells were investigated by immunohistochemistry in 16 human non-functioning-PitNETs (NF-PitNETs) and eight somatotrophinomas, including macrophages (CD68, CD163, HLA-DR), cytotoxic (CD8) and T helper (CD4) lymphocytes, regulatory T cells (FOXP3), B cells (CD20), and neutrophils (neutrophil elastase). Five normal pituitaries were included for comparison. The cytokine secretome from these PitNETs and from PitNET-derived tumour-associated fibroblasts (TAFs) were assessed on culture supernatants using a multiplex immunoassay panel. There were no significant NCAM expression differences between PitNETs and normal pituitary, and no difference between types of pituitary tumours (NF-PitNETs vs. somatotrophinomas). There was no association between NCAM expression and different clinico-pathological features, including cavernous sinus invasion and Ki-67, nor with serum hormone levels. NCAM immunoreactivity correlated negatively with PitNET-derived CXCL10 (rho = -0.417; p = .042) and CX3CL1 (rho = -0.423; p = .040) levels. NCAM immunoreactivity was negatively correlated with TAF-derived fibroblast growth factor (FGF)-2 (rho = -0.632; p = .009), but not with other TAF-derived cytokines. Within the PitNET cohort, there were no correlations between NCAM immunoreactivity and immune infiltrates or ratios, although, within NF-PitNETs, NCAM expression was higher in tumours with more FOXP3+ cells. NCAM expression does not differ between PitNETs and normal pituitary, and does not appear to relate to tumour invasiveness or proliferation. However, our data suggest a possible role for cytokines in the modulation of NCAM expression in PitNETs, particularly CXCL10, CX3CL1 and FGF-2, but not for immune cell infiltrates.

David J Collier 1,2 Pascal Wielders Job van der Palen 4,5 Logan Heyes 6 Dawn Midwinter 6 Kathryn Collison 7 Andy Preece 6 Neil Barnes 1,6 Raj Sharma 1William Harvey Research Institute, Barts & The London School of Medicine &Dentistry, Queen Mary University of London, London, UK; 2Wolfson Institute of Preventive Medicine, Barts & The London School of Medicine & Dentistry, Queen Mary University of London, London, UK; 3Department of Pulmonary Diseases, CatharinaHospital, Eindhoven, Netherlands; 4Department of Pulmonology, Medisch Spectrum Twente, Enschede, Netherlands; 5Department of Research Methodology, Measurement, and Data Analysis, University of Twente, Enschede, Netherlands; 6Respiratory Therapy Area Unit, GlaxoSmithKline Plc., Stockley Park, Uxbridge, UK; 7Respiratory Medical Franchise, GlaxoSmithKline Plc., Research Triangle Park, Durham, NC, USA Introduction: Training in correct inhaler use, ideally in person or by video demonstration, can minimize errors but is rarely provided in clinics. This open-label, low-intervention study evaluated critical error rates with dry-powder inhalers (DPIs), before and after training, in patients with chronic obstructive pulmonary disease. Methods: Patients prescribed an inhaled corticosteroid (ICS)/long-acting β2-agonist (LABA) (ELLIPTA, Turbuhaler, or DISKUS), long-acting muscarinic antagonist (LAMA)/ LABA (ELLIPTA or Breezhaler), or LAMA-only DPI (ELLIPTA, HandiHaler, or Breezhaler) were enrolled. Critical errors were assessed before training (Visit 1 [V1]; primary endpoint) and 6 weeks thereafter (Visit 2 [V2]; secondary endpoint). Logistic regression models were used to calculate odds ratios (ORs) for between-group comparisons. Results: The intent-to-treat population comprised 450 patients. At V1, fewer patients made ≥1 critical error with ELLIPTA (10%) versus other ICS/LABA DPIs (Turbuhaler: 40%, OR 4.66, P=0.005; DISKUS: 26%, OR 2.48, P=0.114) and other LAMA or LAMA/LABA DPIs (HandiHaler: 34%, OR 3.50, P=0.026; Breezhaler: 33%, OR 3.94, P=0.012). Critical error rates with the primary ICS/LABA DPI were not significantly different between ELLIPTA ICS/LABA (10%) and ICS/LABA plus LAMA groups (12–25%). Critical errors with the primary ICS/LABA DPI occurred less frequently with ELLIPTA ICS/LABA with or without LAMA (11%) versus Turbuhaler ICS/LABAwith or without LAMA (39%, OR 3.99, P<0.001) and DISKUS ICS/LABAwith or without LAMA (26%, OR 2.18, P=0.069). Simulating singleinhaler versus multiple-inhaler triple therapy, critical error rates were lower with ELLIPTA fluticasone furoate/vilanterol (FF/VI; 10%) versus ELLIPTA FF/VI plus LAMA (22%), considering errors with either DPI (OR 2.50, P=0.108). At V2, critical error rates decreased for all DPIs/groups, reaching zero only for ELLIPTA. Between-group comparisons were similar to V1. Conclusion: Fewer patients made critical errors with ELLIPTA versus other ICS/LABA, and LAMA or LAMA/LABA DPIs. The effect of “verbal” training highlights its importance for reducing critical errors with common DPIs.