The aim of this study was to elucidate cardiovascular prescriber access, uptake, and attitudes toward CYP2C19 and CYP2D6 genetic testing to guide prescribing of commonly used medications such as clopidogrel, antiarrhythmics, proton pump inhibitors, and antidepressants. A survey, designed in collaboration with the European Society of Cardiology (ESC) WG on Cardiovascular Pharmacotherapy and external experts was disseminated to ESC members using SurveyMonkey. 265 prescribers from 68 countries participated. Most respondents thought testing would be beneficial, though CYP2C19 testing was perceived as more beneficial (73%) and desirable than CYP2D6 (61%). Access to CYP2C19 testing was more common (30%) than CYP2D6 testing (19%), but mostly outside of public funded health systems. Uptake in those who had access was higher for CYP2C19 (67%), than for CYP2D6 (33%). Confidence in interpreting results to prescribe was also higher with CYP2C19 (69%) than with CYP2D6 (53%), but most respondents wanted information prior to prescribing. One third of respondents highlighted the need for a turnaround time that matched their clinical practice. Unsolicited Pharmacogenomic (PGx) information from a patient was uncommon, but most prescribers acted on the information. A minority of respondents had undertaken PGx testing themselves, but most wanted testing for relevant medications. Respondents' experiences as patients made them more likely to believe that PGx testing was warranted. A minority ( ~ 15%) were aware of either local prescriber guidance or patient information materials regarding PGx testing. Prescribers want access to pharmacogenomics data regarding CYP2C19 and CYP2D6 for prescribing cardiovascular medicines. However, there are barriers which hamper implementation. Prescribers lived experience with medication use as patients impacted their views of PGx. 265 prescribers responded to the ESC survey from 68 countries. Most prescribers wanted access to pharmacogenomic testing for CYP2C19 and CYP2D6 for their patients and for themselves. Though most prescribers thought these pharmacogenomic tests would be useful and could improve the risk/benefit profile of relevant medications, prescribers responded more positively to CYP2C19 compared with CYP2D6 testing. Guidance and information for both prescribers and patients were lacking.

Infections of chronic wounds are a major healthcare burden worldwide and can lead to poor health outcomes such as amputations of limbs and death. Detecting infections early significantly increases the effectiveness of therapeutic interventions. Screening of volatile organic compounds (VOCs) emitted from wound swab samples can potentially serve as a highly specific indicator of infection. Profiling of VOCs from infected and non-infected wounds was carried out. Swab samples were collected from 26 wounds from 23 patients (n = 20 diabetic patients; n = 3 non-diabetic patients). There were 16 wounds sampled that were clinically determined as infected, and 10 as non-infected. Headspace-solid phase microextraction gas chromatography-mass spectrometry (HS-GC-MS) was used to rapidly sample and detect VOCs from the swabs following a short incubation period. A total of 42 compounds were identified and included for analysis. Infected wounds emitted more diverse VOCs compared to non-infected wounds. Higher numbers of compounds with significantly higher abundances were detected from severely infected wounds compared to less severely infected wounds. Abundances of short-chain fatty acids (SCFAs) and branched-chain fatty acids (BCFAs) were found to be the strongest discriminators of infected from non-infected wounds. Further validation is needed, but the results of this pilot study highlight the potential of detecting these compounds as a highly specific and targeted route to predicting or detecting wound infections in the future.

Direct-to-consumer (DTC) pharmacogenomic (PGx) testing is expanding rapidly in the UK, yet no dedicated regulatory framework currently governs these services. Although a 2021 parliamentary inquiry recommended stronger safeguards and clearer technical standards for genomic testing, these proposals have not been applied to PGx. This study explores public attitudes toward DTC PGx testing, focusing on expectations for pre-test information, quality standards, and NHS data use. We conducted focus groups with members of the public, both with and without prior experience of purchasing DTC PGx tests, or other online health tests. Focus groups were audio-recorded with consent, transcribed, and analysed thematically. We identified three themes: (mis)understanding towards and awareness of DTC PGx testing; altruistic motivation and equity concerns; and (mis)trust. Participants were generally enthusiastic about PGx testing, as long as issues of equity, data protection, and regulation were addressed, with data sharing concerns being particularly prominent.

The aim of this study was to describe self-reported use of medications with established pharmacogenetic guidance in the Our Future Health (OFH) cohort. We examined four key pharmacogenes-CYP2C19, CYP2C9, CYP2D6, and SLCO1B1-and medications supported by strong evidence for clinical actionability according to the Clinical Pharmacogenetics Implementation Consortium (CPIC). Self-reported medication use was summarized, concurrent use assessed, and findings stratified by age, sex, and ethnicity. We studied these data in 1.78 million OFH participants included in the June 2025 release. The cohort was 57.3% female, aged 18-95 years (mean 53.1 years), with 90.2% self-identifying as "White." Eighteen medication groups were explicitly listed in the baseline questionnaire, enabling identification of exposure at group level rather than for individual drugs. Medication groups with pharmacogenetic relevance included antidepressants (selective serotonin reuptake inhibitors and tricyclics), statins, proton pump inhibitors, ibuprofen, opioids, clopidogrel, and warfarin. Overall, 25.2% of participants (N = 449,641) reported use of at least one such group. These users tended to be older, more frequently female, and reported more comorbidities than non-users. Concurrent exposure to two or more pharmacogenetically actionable medications metabolized by different genes was common, occurring in 37% of users. A substantial proportion of the OFH cohort therefore reported exposure to medications with pharmacogenetic guidance. Use was observed across all ages, with prevalence increasing with age. With continued expansion of the cohort and future linkage to prescribing records, OFH will provide a critical resource for population-scale pharmacogenetic research.

Aminoglycosides are broad-spectrum antibiotics used in the management of severe infections. Aminoglycosides are associated with nephrotoxicity and ototoxicity. Although dosing strategies such as once-daily administration and therapeutic drug monitoring have reduced the incidence of nephrotoxicity, ototoxicity remains unpredictable and may occur at therapeutic concentrations. A strong association between specific mitochondrial DNA variants in MT-RNR1 (m.1555A > G, m.1494C > T and m.1095 T > C) and aminoglycoside-induced hearing loss exists. These variants (frequency ~1 in 330 individuals across populations) predispose to irreversible, sensorineural hearing loss following aminoglycoside exposure, sometimes after a single dose. Avoidance of aminoglycosides is recommended at any detectable variant level. In England, laboratory-based MT-RNR1 testing is nationally commissioned, whereas point-of-care testing in time-critical settings like neonatal sepsis is delivered in some centres. Approximately 20% of aminoglycoside use is predictable providing opportunities for pre-emptive pharmacogenetic testing. Where MT-RNR1 testing results are unavailable and clinical urgency is high, aminoglycoside treatment should not be delayed. Early health economic evidence suggests that point-of-care testing in neonates may be cost-saving by preventing lifelong hearing loss. Regulatory and Health Technology Assessment bodies support targeted implementation of testing alongside further evidence generation. Overall, integration of MT-RNR1 pharmacogenetic testing offers a feasible and proportionate strategy to reduce harm while preserving access to life-saving antibiotic therapy. This guideline is grounded in the latest evidence in this field but cannot account for all individual factors relevant to patient care. Therefore, prescribers must conduct a thorough assessment of each patient's risk-benefit profile, ensuring that therapy is optimized to maximize benefits while minimizing potential harms.

Pharmacogenomics holds promise for enhancing drug safety and efficacy, paving the way for more precise, patient-centered therapeutic approaches and supporting personalized medicine and prevention. However, its routine integration into healthcare remains limited. A European multidisciplinary expert workshop was held in Amsterdam in January 2025, to share experiences regarding the priorities to further implement pharmacogenomic-guided treatment and prevention into clinical practice. A qualitative content analysis was conducted to identify key themes to support improved implementation of pharmacogenomics. The analysis drew on inputs from a multi-stakeholder workshop involving 55 participants from 10 European countries, representing policy, healthcare, academia, patient organizations and industry. The paper is centered around three central pillars to implement pharmacogenomics: evidence, acceptance, and integration into healthcare systems. Based on the expert presentations and discussions, five key priorities were identified for advancing pharmacogenomics: 1) the need for robust clinical and health economic evaluations to support funding and reimbursement decisions, 2) education and training for healthcare professionals, and raising awareness of pharmacogenomics among policymakers and the public, 3) investment in information technology and data infrastructure for interoperable storage and clinical decision making, 4) harmonizing regulatory and reimbursement policies, and 5) ensuring equitable access of pharmacogenomics. Findings underscore the need of a closer alignment through e.g. a dedicated network to move pharmacogenomics from an emerging innovation to a standard component of personalized medicine across Europe. Multidisciplinary collaboration throughout the implementation pathway will be crucial to advance pharmacogenomic-guided treatment and prevention as key part of personalized medicine.

Type 2 diabetes (T2D) is a highly prevalent condition worldwide. Many patients with T2D monitor blood glucose regularly to guide their diabetes management. In recent years continuous glucose monitoring (CGM) has emerged as a promising alternative to traditional self-monitoring of blood glucose (SMBG). CGM can result in improved glycemic control, fewer diabetes-related hospital admissions and improved quality of life. In Ireland, however, CGM is not currently reimbursed for people with T2D, even those who are insulin-treated. The goal of the present study was to examine the glucose monitoring modalities used by patients attending diabetes outpatient clinics in a secondary care setting in Ireland. The proportions using SMBG and CGM and the patients' diabetes medications were recorded. Data were collected through a self-administered survey from participants attending outpatient diabetes clinics. We found that, of 137 patients surveyed, only 17 (12%) were using CGM for blood glucose monitoring, while 102 (75%) were using SMBG; the remainder were not testing glucose. Amongst 45 patients on insulin therapy, 15 (33%) were using a CGM, and 29 (64%) were using SMBG. This study highlights that a preponderance of patients with T2D in a representative Irish secondary care cohort do not use CGM for blood glucose monitoring, even amongst those on insulin therapy. These findings underscore the lack of access to CGM amongst patients with T2D on insulin in Ireland, which is potentially compromising their level of care and quality of life.

Pharmacogenetics uses genetic testing to improve the safety and effectiveness of prescribed medicines, yet implementation at scale remains limited due to the absence of interoperable health IT solutions that integrate results into prescribing workflows. This study aimed to develop and validate open data standards for pharmacogenetic results to enable interoperability across healthcare systems. A baseline data model was constructed using the open standard openEHR by synthesising literature, genomic sequencing outputs, and international data specifications, and refined through iterative workshops with the Global Alliance for Genomics and Health. The model underwent two rounds of structured peer review involving 24 experts from 10 countries. Mapping to HL7 FHIR was evaluated using both manual and automated approaches, including the FHIR-Connect tool. The resulting standardised pharmacogenetic data model separates test results from therapeutic implications and incorporates recognised terminologies such as SNOMED CT and HGNC. It achieved international consensus and is published on the openEHR Clinical Knowledge Manager platform. Mapping to HL7 FHIR demonstrated bidirectional information flow within healthcare systems, with automated mapping enabling scalable and reusable transformations. This work provides a framework for storing and exchanging pharmacogenetic test results, supporting semantic harmonisation, interoperability, and integration with clinical decision support systems. Open data standards for pharmacogenetic test results therefore offer a foundation for scalable implementation of pharmacogenetics in routine clinical practice.

Background Enhanced Community Care (ECC) for type 2 diabetes mellitus (T2DM) in Ireland introduces episodic, community-based, consultant-led multidisciplinary care of diabetes that in turn supports the general practitioner (GP)-delivered chronic disease management programme (CDMP). The Dublin North West (DNW) hub, Ireland’s first fully operational ECC hub, began providing its diabetes service in March 2023. Aims This study reviewed the first year of the DNW hub’s diabetes operations, focusing on referral patterns, patient demographics, clinical characteristics, and CDMP eligibility (only those people living with T2DM with a medical card or a GP visit card are eligible for CDMP for T2DM; otherwise, people living with T2DM must self-pay for GP-provided T2DM care). Methods A retrospective analysis was conducted on patient charts and hospital databases for all referrals to the DNW hub from March 2023 to March 2024. Results Out of 204 referrals, 67% were redirected from hospital waiting lists, 22% were direct GP referrals, and 11% were internal from other hub services. The average wait time from referral to first appointment was 8.6 weeks. Attendees were 44% female and 56% male, with an average age of 56.2 years. Notably, only 46% were eligible for CDMP. During the study period, the number of people living with T2DM waiting for diabetes appointments at Connolly Hospital decreased by 61%, with the average waiting time reduced from 11 to 5 months. Conclusions The first year of activity in the DNW hub illustrates the potential of the ECC model to positively impact hospital waiting lists. Our data also suggests that eligibility to access the CDMP may merit expansion as part of the ongoing implementation of ECC in Ireland.

Background: Why some individuals experience severe neuropathy following infection is unknown. Nucleocytoplasmic trafficking (NCT) is an essential process in nucleated cells, and its disruption has been implicated in many neurodegenerative conditions including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. Methods: We performed genomic and clinical studies in 24 individuals from 12 families with acute onset axonal neuropathy. Genetic variants were characterized by thermal stability and enzymatic assays using recombinantly expressed protein. Protein localization was determined in patient fibroblasts using immunofluorescence following heat or oxidative stress. A humanized Drosophila model was generated to determine the effect of stress on in vivo function. Results: We identified deleterious biallelic variants in human RCC1, encoding a GTP exchange factor essential in maintaining Ran GTPase-dependent NCT function. Clinical presentations ranged from a rapidly progressive, fatal axonal neuropathy with encephalopathy to a mild motor neuropathy resulting in impaired walking. In most patients (n=22/24), neurological presentation was secondary to infection, resulting in prior diagnosis of Guillain-Barre syndrome (GBS) in 13. The efficiency of cellular Ran GDP-GTP exchange and the thermal stability of Rcc1 protein was reduced by disease-associated variants. Heat shock or oxidative stress revealed defects in Ran nuclear localization, impaired NCT, and TDP-43 mislocalization in patient fibroblasts. Disease associated variants were unable to rescue the thermosensitive phenotype of a rcc1 deficient hamster cell line. RCC1 Drosophila models revealed a fatal intolerance to oxidative stress. Conclusion: We describe a novel autosomal recessive acute onset axonal neuropathy triggered by infection caused by biallelic RCC1 variants, which mimics GBS and has important mechanistic overlap with ALS. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement We acknowledge grant support from: the Wellcome Trust ; the Manchester NIHR BRC (NIHR203308); LifeArc Pathfinder award; and NIHR Doctoral Fellow, 301748). This research was made possible through access to data in the National Genomic Research Library, which is managed by Genomics England Limited (a wholly owned company of the Department of Health and Social Care). The National Genomic Research Library holds data provided by patients and collected by the NHS as part of their care and data collected as part of their participation in research. The National Genomic Research Library is funded by the National Institute for Health Research and NHS England. The Wellcome Trust, Cancer Research UK and the Medical Research Council have also funded research infrastructure. Further acknowledgements of funding are provided in the supplementary appendix. A.B. is supported by a Wellcome PhD Training Fellowship for Clinicians and the 4Ward North PhD Programme for Health Professionals (223521/Z/21/Z). P.L. is supported by Ministry of Health of the Czech Republic, grant. no: NW24-04-00349. R.H. is supported by the Wellcome Discovery Award (226653/Z/22/Z), the Medical Research Council (UK) (MR/V009346/1), the Addenbrookes Charitable Trust (G100142), the Hereditary Neuropathy Foundation, the Stoneygate Trust, the Lily Foundation, Ataxia UK, Action for AT, the Muscular Dystrophy UK, the LifeArc Centre to Treat Mitochondrial Diseases (LAC-TreatMito) and the UKRI/Horizon Europe Guarantee MSCA Doctoral Network Programme (Project 101120256: MMM). This research was supported by the NIHR Cambridge Biomedical Research Centre (BRC-1215-20014). The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care. H.L. receives support from the Canadian Institutes of Health Research (CIHR) for Foundation Grant FDN-167281 (Precision Health for Neuromuscular Diseases), Transnational Team Grant ERT-174211 (ProDGNE) and Network Grant OR2-189333 (NMD4C), from the Canada Foundation for Innovation (CFI-JELF 38412), the Canada Research Chairs program (Canada Research Chair in Neuromuscular Genomics and Health, 950-232279), the European Commission (Grant # 101080249) and the Canada Research Coordinating Committee New Frontiers in Research Fund (NFRFG-2022-00033) for SIMPATHIC, and from the Government of Canada Canada First Research Excellence Fund (CFREF) for the Brain-Heart Interconnectome (CFREF-2022-00007). RWT is funded by the Wellcome Centre for Mitochondrial Research (203105/Z/16/Z), the Mitochondrial Disease Patient Cohort (UK) (G0800674), the Medical Research Council (MR/W019027/1), the Lily Foundation, the Pathological Society, the UK NIHR Biomedical Research Centre for Ageing and Age-related disease award to the Newcastle upon Tyne Foundation Hospitals NHS Trust, LifeArc and the UK NHS Highly Specialised Service for Rare Mitochondrial Disorders of Adults and Children. R.D.S.P. is funded by The Lily Foundation, Muscular Dystrophy UK (MDUK), and a seedcorn award from the Rosetrees Trust and Stoneygate Foundation. R.D.S.P. is supported by a Medical Research Council (UK) Transition Support award (MR/X02363X/1), Medical Research Council (UK) award MC\_PC\_21046 to establish a National Mouse Genetics Network Mitochondria Cluster (MitoCluster), and the LifeArc Centre to Treat Mitochondrial Diseases (LAC-TreatMito). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Written informed consent was obtained from all persons in the study (or from their parents or guardians) in accordance with the Declaration of Helsinki protocols, and our experimental protocols were approved by the NHS institutional review board (IRAS 64321). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors

INTRODUCTION:Patients with chronic limb-threatening ischaemia (CLTI) are often prescribed clopidogrel in order to reduce their risk of major adverse limb and cardiovascular events. Clopidogrel is metabolised by the CYP2C19 enzyme and genetic variations in CYP2C19 are common. These variants can influence an individual's ability to metabolise clopidogrel to its active metabolite. Few studies have investigated the relationship between patient genotype and outcomes in vascular surgery. This work aims to establish the relationship between patient genotype and outcomes after revascularisation in patients with CLTI who are prescribed clopidogrel. It will consider whether pharmacogenetics can be used to ensure patients are prescribed effective medications to optimise their outcomes. METHODS AND ANALYSIS:This is an observational cohort study of patients undergoing lower limb surgical, endovascular or hybrid revascularisation for CLTI at Manchester University NHS Foundation Trust. Patients taking clopidogrel post-procedure, as well as those prescribed a non-clopidogrel based medication regimen, will be recruited prior to or shortly after revascularisation. Patients will undergo CYP2C19 genotyping and will be followed up using online records. The study has 90% power to detect 114 amputations with a target sample size of 483 participants. The primary outcomes are risk of amputation at 1 year and a composite endpoint for the risk of major adverse limb events (MALE) or death from any cause at 1 year. Secondary outcomes are risk of MALE at 1 year, risk of major adverse cardiovascular events (MACE) or death from any cause at 1 year, death within 30 days of revascularisation, minor re-interventions at 1 year, total number of re-interventions at 1 year and rate of systemic or gastrointestinal bleed at 1 year.Risk of amputation, MALE and MACE will be analysed using Cox models. All remaining outcomes will be analysed using negative binomial models. Potential competing events for the risk of amputation will be investigated as part of a sensitivity analysis. Patients given a non-clopidogrel-based medication will be compared as an additional analysis. ETHICS AND DISSEMINATION:Manchester University Research Ethics Committee approval obtained as part of the Implementing Pharmacogenetics to Improve Prescribing (IPTIP) trial process (IRAS 305751). The results of the study will be published in a peer-reviewed journal and presented at international conferences. REGISTRATION:This work is a sub-protocol for the IPTIP study which is registered as ISRCTN14050335.

Over the past decade there has been considerable and growing enthusiasm about the promise of using genomics to inform healthcare. In particular, using genetic data to inform prescribing practice has emerged as a compelling policy priority for health systems around the world, not least in the NHS. Various initiatives and strategies have been developed to explore the value of pharmacogenomics in the UK National Health Service (NHS) and identify strategies for implementation. The NHS England Network of Excellence for Pharmacogenomics and Medicines Optimisation (PGx-NoE) was launched in 2024 and held two stakeholder meetings over the year in collaboration with the UK Pharmacogenetics and Stratified Medicine Network and the British Pharmacological Society (BPS). This article describes the outputs of those meetings, which are discussed in the context of previously identified challenges and opportunities. Rather than simply identify further barriers or facilitators, outputs are contextualized around tangible recommendations and real-world implementation exercises. These are grouped into three key areas: genetics, data and service. The work of partners across the UK are highlighted, including development of the NHS England Genomic Test Directory, the proof-of-principle informatic patterns demonstrated by the PROGRESS study, and the launch of the Centre for Excellence in Regulatory Science and Innovation (CERSI) in Pharmacogenomics, which will create UK-specific guidance and clarify complex regulatory pathways. Many of the well-defined barriers to the implementation of pharmacogenomics have been addressed in recent years, and this work highlights how the UK has the opportunity to emerge as a global leader in genomics-informed healthcare.

Background: Variation in DNA is known to contribute to medication response, impacting both medicine effectiveness and incidence of adverse drug reactions (ADRs). However, clinical implementation of pharmacogenomics (PGx) has been slow, and the views of the public are not well understood. Aim: To assess UK national public attitudes around pharmacogenetics. Design and Methods: The survey was co-designed with the Participant Panel at Genomics England and the data were collected by the National Centre for Social Research, using its nationally representative panel of UK adults. Multivariable logistic regression analyses were used to analyse relationships between selected survey reported variables, controlled for age and sex. Results: The survey response rate was 58%. Two thousand seven hundred and nineteen responses were obtained. Most respondents (59%) had experienced either no benefit or a side effect. Forty-five per cent of respondents reported having experienced no benefit and 46% of respondents reported having experienced a side effect, with female respondents more likely to be in both groups (P < 0.0001). Despite variability in interindividual medicine response being well understood (89%), the involvement of DNA in predicting benefit or risk of a side effect is not (understood by 52% and 48%, respectively). Eighty-nine per cent would complete a PGx test, with 91% wanting direct access to this information. Eighty-five per cent of UK adults think that the NHS should offer PGx to those regularly taking many medicines. Respondents were not more worried overall about misuse of PGx data compared with other routine medical data. Experience with prescription medication impacted on views with those who were prescribed medication almost twice as likely to want a PGx test for any reason. Conclusion: Most respondents reported experience with either a medication not working for them or ADRs. There was a high level of understanding of variable medication response but a relatively low level of awareness of the role genetics plays in that variability. Most respondents would want a PGx test, to have direct access to results, and think the NHS should offer this form of testing. Importantly, respondents were not more concerned about PGx data use than that of any other routinely generated medical data. Notably, this study highlights a relationship between individuals' experiences with prescription medications and their interest in PGx testing, underscoring the potential for personalized medicine to address public healthcare needs.