Understanding general practitioner and pharmacist preferences for pharmacogenetic testing in primary care: a discrete choice experiment.

Pharmacogenetic testing in the United Kingdom's National Health Service (NHS) has historically been reactive in nature, undertaken in the context of single gene-drug relationships in specialist settings. Using a discrete choice experiment we aimed to identify healthcare professional preferences for development of a pharmacogenetic testing service in primary care in the NHS. Respondents, representing two professions groups (general practitioners or pharmacists), completed one of two survey versions, asking them to select their preferred pharmacogenetic testing service in the context of a presentation of low mood or joint pain. Responses from 235 individuals were included. All respondents preferred pharmacogenetic testing over no testing, though preference heterogeneity was identified. Both professional groups, but especially GPs, were highly sensitive to service design, with uptake varying depending on the service offered. This study demonstrates uptake of a pharmacogenetic testing service is impacted by service design and highlights key areas which should be prioritised within future initiatives.

Irregular breakfast eating in type 2 diabetes mellitus is associated with greater social jetlag and poorer metabolic health.

Circadian disruption, arising from conflict between internal circadian time and behavioural sleep-wake and fasting-feeding rhythms, may contribute to the prevalence of type 2 diabetes mellitus and disease severity. Previous studies have demonstrated a link between irregular breakfast eating and poorer metabolic health. We aimed to further explore the relationships between breakfast habits, circadian misalignment (social jetlag), and metabolic parameters in a cohort of adult participants with type 2 diabetes mellitus. A total of 330 adult participants with type 2 diabetes mellitus attending for routine clinical review completed structured questionnaires to assess habitual sleep timing, chronotype, and social jetlag. Statistical analysis was via inferential groupwise approaches and path analysis to establish interdependencies of effects of social jetlag, chronotype, and breakfast eating regularity on HbA1c. 22.7% of the participants reported eating breakfast five times or fewer a week, and were categorised as irregular breakfast eaters. Compared with those who ate breakfast six or seven times a week, irregular breakfast eaters had significantly higher HbA1c and diastolic blood pressure, were younger and had greater social jetlag. In the path analysis, irregular breakfast eating exerted a direct effect on HbA1c, whilst social jetlag exerted only an indirect effect on HbA1c through breakfast eating regularity. Chronotype did not exert any effect on HbA1c, but did exert an indirect effect on breakfast eating regularity via social jetlag. Our results showed that adult participants with type 2 diabetes mellitus, who ate breakfast irregularly had poorer metabolic health and greater social jetlag. The relationship between social jetlag and glycaemic control appears to be mediated through breakfast eating habits.

Public preferences for pharmacogenetic testing in the NHS: Embedding a discrete choice experiment within service design to better meet user needs.

AIMS: Genetic testing can be used to improve the safety and effectiveness of commonly prescribed medicines-a concept known as pharmacogenetics. This study aimed to quantify members of the UK public's preferences for a pharmacogenetic service to be delivered in primary care in the National Health Service. METHODS: Members of the UK population were surveyed via an online panel company. Respondents completed 1 of 2 survey versions, asking respondents to select their preferred pharmacogenetic testing service in the context of a presentation of low mood or pain. A conditional logit model was estimated, before the best functional form for the dataset was identified. Preference heterogeneity was identified via latent class analysis. Coefficients from the final selected models were used to estimate uptake in the context of different hypothetical pharmacogenetic services. RESULTS: Responses from 1993 individuals were included in the analysis. There were no differences observed in preference between the 2 clinical scenarios. Conditional logit analysis, using maximum likelihood estimation, indicated that respondents preferred to have noninvasive tests and wanted their data to be shared between different healthcare organizations to guide future prescribing. There was a preference for regional over national data sharing initiatives, and respondents preferred to have access to their data. Predicted uptake varied considerably, ranging from 51% to >99%, depending on design of the service. CONCLUSION: This study identifies public preferences for a pharmacogenetic testing service and demonstrates how predicted uptake can be impacted by relatively minor adaptations. This highlights areas for prioritization during development of future pharmacogenetic services.

The impact of machine learning on the prediction of diabetic foot ulcers - A systematic review.

INTRODUCTION: Globally, diabetes mellitus poses a significant health challenge as well as the associated complications of diabetes, such as diabetic foot ulcers (DFUs). The early detection of DFUs is important in the healing process and machine learning may be able to help inform clinical staff during the treatment process. METHODS: A PRISMA-informed search of the literature was completed via the Cochrane Library and MEDLINE (OVID), EMBASE, CINAHL Plus and Scopus databases for reports published in English and in the last ten years. The primary outcome of interest was the impact of machine learning on the prediction of DFUs. The secondary outcome was the statistical performance measures reported. Data were extracted using a predesigned data extraction tool. Quality appraisal was undertaken using the evidence-based librarianship critical appraisal tool. RESULTS: A total of 18 reports met the inclusion criteria. Nine reports proposed models to identify two classes, either healthy skin or a DFU. Nine reports proposed models to predict the progress of DFUs, for example, classing infection versus non-infection, or using wound characteristics to predict healing. A variety of machine learning techniques were proposed. Where reported, sensitivity = 74.53-98 %, accuracy = 64.6-99.32 %, precision = 62.9-99 %, and the F-measure = 52.05-99.0 %. CONCLUSIONS: A variety of machine learning models were suggested to successfully classify DFUs from healthy skin, or to inform the prediction of DFUs. The proposed machine learning models may have the potential to inform the clinical practice of managing DFUs and may help to improve outcomes for individuals with DFUs. Future research may benefit from the development of a standard device and algorithm that detects, diagnoses and predicts the progress of DFUs.

Utility of screening for silent myocardial ischaemia in diabetes with an annual electrocardiogram.

BACKGROUND AND METHODS: Asymptomatic coronary artery disease (CAD) is common in people with diabetes mellitus, but there is a lack of consensus regarding appropriate screening for the condition. We performed a 12-lead electrocardiogram (ECG) on 312 consecutive participants with diabetes mellitus attending for routine annual outpatient review in order to determine the effectiveness of a yearly ECG in screening people with diabetes for asymptomatic CAD. RESULTS: Three of 312 participants (0.96%, 95% CI 0.2%-2.78%) had a newly identified ECG abnormality. One person had newly discovered atrial fibrillation. Two people had abnormalities which prompted further investigation for asymptomatic CAD. One of these participants underwent percutaneous coronary intervention. Seventeen further participants had abnormalities on ECG which had been previously documented, the majority having been present since their diagnosis of diabetes. CONCLUSION: A low positive yield of routine annual ECG in our study does not support its use as a screening tool for asymptomatic CAD in diabetes. Our findings support advice to perform an ECG at diagnosis of diabetes and to repeat only if a person develops relevant symptoms.

The Implementation of Pharmacogenetics in the United Kingdom.

There is considerable inter-individual variability in the effectiveness and safety of pharmaceutical interventions. This phenomenon can be attributed to a multitude of factors; however, it is widely acknowledged that common genetic variation affecting drug absorption or metabolism play a substantial contributory role. This is a concept known as pharmacogenetics. Understanding how common genetic variants influence responses to medications, and using this knowledge to inform prescribing practice, could yield significant advantages for both patients and healthcare systems. Some health services around the world have introduced pharmacogenetics into routine practice, whereas others are less advanced along the implementation pathway. This chapter introduces the field of pharmacogenetics, the existing body of evidence, and discusses barriers to implementation. The chapter will specifically focus on efforts to introduce pharmacogenetics in the NHS, highlighting key challenges related to scale, informatics, and education.

Mutations in PCYT2 disrupt etherlipid biosynthesis and cause a complex hereditary spastic paraplegia.

CTP:phosphoethanolamine cytidylyltransferase (ET), encoded by PCYT2, is the rate-limiting enzyme for phosphatidylethanolamine synthesis via the CDP-ethanolamine pathway. Phosphatidylethanolamine is one of the most abundant membrane lipids and is particularly enriched in the brain. We identified five individuals with biallelic PCYT2 variants clinically characterized by global developmental delay with regression, spastic para- or tetraparesis, epilepsy and progressive cerebral and cerebellar atrophy. Using patient fibroblasts we demonstrated that these variants are hypomorphic, result in altered but residual ET protein levels and concomitant reduced enzyme activity without affecting mRNA levels. The significantly better survival of hypomorphic CRISPR-Cas9 generated pcyt2 zebrafish knockout compared to a complete knockout, in conjunction with previously described data on the Pcyt2 mouse model, indicates that complete loss of ET function may be incompatible with life in vertebrates. Lipidomic analysis revealed profound lipid abnormalities in patient fibroblasts impacting both neutral etherlipid and etherphospholipid metabolism. Plasma lipidomics studies also identified changes in etherlipids that have the potential to be used as biomarkers for ET deficiency. In conclusion, our data establish PCYT2 as a disease gene for a new complex hereditary spastic paraplegia and confirm that etherlipid homeostasis is important for the development and function of the brain.

ALTERATIONS IN THYROID HORMONE LEVELS FOLLOWING GROWTH HORMONE REPLACEMENT EXERT COMPLEX BIOLOGICAL EFFECTS.

OBJECTIVE: Alterations in the thyroid axis are frequently observed following growth hormone (GH) replacement, but uncertainty exists regarding their clinical significance. We aimed to compare fluctuations in circulating thyroid hormone levels, induced by GH, to changes in sensitive biological markers of thyroid hormone action. METHODS: This was a prospective observational clinical study. Twenty hypopituitary men were studied before and after GH replacement. Serum thyroid-stimulating hormone (TSH), thyroid hormones, and insulin-like growth factor 1 were measured. Changes in thyroid hormone concentrations were compared to alterations in resting metabolic rate and cardiac time intervals. Health-related quality of life (QOL) was assessed by disease-sensitive and generic questionnaires. RESULTS: Following GH replacement, free thyroxine concentration declined and free triiodothyronine level increased. Resting energy expenditure increased, particularly in subjects with profound hypopituitarism, including TSH deficiency (16.73 ± 1.75 kcal/kg/min vs. 17.96 ± 2.26 kcal/kg/min; P = .01). Alterations in the thyroid axis were more pronounced in subjects with a low/normal baseline respiratory quotient (RQ) who experienced a paradoxical rise in RQ (0.81 vs. 0.86; P = .01). Subjects with a high baseline RQ experienced a slight but nonsignificant fall in RQ without alteration in thyroid axis. The isovolumetric contraction time was shortened during the study; however, this did not reach statistical significance. Improvements in QOL were observed despite alterations in thyroid axis. CONCLUSION: Changes in the thyroid axis following GH replacement are associated with complex tissue-specific effects. These fluctuations may induce a hypothyroid phenotype in some tissues while appearing to improve the biological action of thyroid hormone in other organs. ABBREVIATIONS: AGHDA = Assessment of Growth Hormone Deficiency in Adulthood; CHOox = carbohydrate oxidation; ET = ejection time; fT3 = free triiodothyronine; fT4 = free thyroxine; GH = growth hormone; GHD = growth hormone deficiency; HB-RQ = high baseline respiratory quotient; HPT = hypothalamic-pituitary-thyroid; ICT = isovolumetric contraction time; IGF-1 = insulin-like growth factor 1; IRT = isovolumetric relaxation time; LB-RQ = low baseline respiratory quotient; LV = left ventricular; NHP = Nottingham Health Profile; QOL = quality of life; REE = resting energy expenditure; RQ = respiratory quotient; rT3 = reverse triiodothyronine; SF-36 = Short Form 36; TSH = thyroid-stimulating hormone; T3 = triiodothyronine; T4 = thyroxine; TT3 = total triiodothyronine; TT4 = total thyroxine.

Clocks in the clinic: circadian rhythms in health and disease.

Circadian rhythms are endogenously generated recurring patterns of around 24 hours with well-established roles in physiology and behaviour. These circadian clocks are important in both the aetiology and treatment of various psychiatric and metabolic diseases. To maintain physiological homeostasis and optimal functioning, living life synchronised to these clocks is desirable; modern society, however, promotes a '24/7' lifestyle where activity often occurs during the body's 'biological night', resulting in mistimed sleep and circadian misalignment. This circadian desynchrony can increase the risk of disease and can also influence treatment response. Clinicians should be aware of the influence that circadian desynchrony can have on health and disease, in order to potentially develop new therapeutic strategies and to incorporate chronotherapeutics into current treatment strategies to enhance their utility.

The effect of growth hormone replacement on the thyroid axis in patients with hypopituitarism: in vivo and ex vivo studies.

OBJECTIVE: Alterations in the hypothalamic-pituitary-thyroid axis have been reported following growth hormone (GH) replacement. The aim was to examine the relationship between changes in serum concentration of thyroid hormones and deiodinase activity in subcutaneous adipose tissue, before and after GH replacement. DESIGN: A prospective, observational study of patients receiving GH replacement as part of routine clinical care. PATIENTS: Twenty adult hypopituitary men. MEASUREMENTS: Serum TSH, thyroid hormones - free and total thyroxine (T4) and triiodothyronine (T3) and reverse T3, thyroglobulin and thyroid-binding globulin (TBG) levels were measured before and after GH substitution. Changes in serum hormone levels were compared to the activity of deiodinase isoenzymes (DIO1, DIO2 and DIO3) in subcutaneous adipose tissue. RESULTS: The mean daily dose of growth hormone (GH) was 0·34 ± 0·11 mg (range 0·15-0·5 mg). Following GH replacement, mean free T4 levels declined (-1·09 ± 1·99 pmol/l, P = 0·02). Reverse T3 levels also fell (-3·44 ± 1·42 ng/dl, P = 0·03) and free T3 levels increased significantly (+0·34 ± 0·15 pmol/l, P = 0·03). In subcutaneous fat, DIO2 enzyme activity declined; DIO1 and DIO3 activities remained unchanged following GH substitution. Serum TSH, thyroglobulin and TBG levels were unaltered by GH therapy. CONCLUSIONS: In vitro analysis of subcutaneous adipose tissue from hypopituitary human subjects demonstrates that GH replacement is associated with significant changes in deiodinase isoenzyme activity. However, the observed variation in enzyme activity does not explain the changes in the circulating concentration of thyroid hormones induced by GH replacement. It is possible that deiodinase isoenzymes are differentially regulated by GH in other tissues including liver and muscle.

Genomics and insurance in the United Kingdom: increasing complexity and emerging challenges.

This article identifies issues relating to the use of genetics and genomics in risk-rated insurance that may challenge existing regulatory models in the UK and elsewhere. We discuss three core issues: (1) As genomic testing advances, and results are increasingly relevant to guide healthcare across an individual's lifetime, the distinction between diagnostic and predictive testing that the current UK insurance code relies on becomes increasingly blurred. (2) The emerging category of pharmacogenetic tests that are predictive only in the context of a specific prescribing moment. (3) The increasing availability and affordability of polygenic scores that are neither clearly diagnostic nor highly predictive, but which nonetheless might have incremental value for risk-rated insurance underwriting beyond conventional factors. We suggest a deliberative approach is required to establish when and how genetic information can be used in risk-rated insurance.

Pre-Emptive Pharmacogenetic Testing in the Acute Hospital Setting: A Cross-Sectional Study.

BACKGROUND: Pharmacogenetic guided prescribing can be used to improve the safety and effectiveness of medicines. There are several approaches by which this intervention might be implemented in clinical practice, which will vary depending on the health system and clinical context. AIM: To understand the clinical utility of panel-based pharmacogenetic testing in patients admitted acutely to hospital and to establish variables which predict if an individual might benefit from the intervention. DESIGN: A cross-sectional study recruiting patients admitted acutely to hospital. METHODS: Participants underwent panel-based pharmacogenetic testing and their genetic results were analysed in their context of the medicines they had been exposed to as an inpatient. The primary outcome was the proportion of patients with clinically actionable gene-drug interactions. Individual variables which predict the clinical utility of pharmacogenetic testing were established via logistic regression. RESULTS: Genetic and prescribing data were available for 482 in-patients (55% male; median age 61.2 years; range: 18 to 96), 97.9% of whom carried a pharmacogenetic result of interest. During their admission, 79.5% of patients were exposed to a medicine for which there is pharmacogenetic prescribing guidance available. Just under 1 in 7 individuals (13.7%) had a clinically actionable gene-drug interaction. Increasing age (> 50-years) was positively correlated with the likelihood (2.7-fold increased risk) of having a clinically actionable interaction. CONCLUSIONS: These findings demonstrate the potential scale, and potential clinical utility, of pharmacogenetic testing as an intervention, highlighting the need to develop infrastructure to support healthcare professionals make use of this emerging tool.

A metabolic signature for NADSYN1-dependent congenital NAD deficiency disorder.

Nicotinamide adenine dinucleotide (NAD) is essential for embryonic development. To date, biallelic loss-of-function variants in 3 genes encoding nonredundant enzymes of the NAD de novo synthesis pathway - KYNU, HAAO, and NADSYN1 - have been identified in humans with congenital malformations defined as congenital NAD deficiency disorder (CNDD). Here, we identified 13 further individuals with biallelic NADSYN1 variants predicted to be damaging, and phenotypes ranging from multiple severe malformations to the complete absence of malformation. Enzymatic assessment of variant deleteriousness in vitro revealed protein domain-specific perturbation, complemented by protein structure modeling in silico. We reproduced NADSYN1-dependent CNDD in mice and assessed various maternal NAD precursor supplementation strategies to prevent adverse pregnancy outcomes. While for Nadsyn1+/- mothers, any B3 vitamer was suitable to raise NAD, preventing embryo loss and malformation, Nadsyn1-/- mothers required supplementation with amidated NAD precursors (nicotinamide or nicotinamide mononucleotide) bypassing their metabolic block. The circulatory NAD metabolome in mice and humans before and after NAD precursor supplementation revealed a consistent metabolic signature with utility for patient identification. Our data collectively improve clinical diagnostics of NADSYN1-dependent CNDD, provide guidance for the therapeutic prevention of CNDD, and suggest an ongoing need to maintain NAD levels via amidated NAD precursor supplementation after birth.

Thematic Daily Sleep Routine Analysis of Adults Not in Employment Living with Type 2 Diabetes Mellitus.

BACKGROUND: Day-to-day variations in sleep timing have been associated with poorer glycemic control in type 2 diabetes mellitus, although the factors that influence this sleep timing variability are poorly understood. METHODS: Daily routines of sleep in a sample of seventeen adults with type 2 diabetes mellitus who were either retired or not currently working were examined qualitatively through the application of semi-structured interviews and a thematic analysis of the resulting transcripts. RESULTS: Four themes were identified: "Consistent Sleeping Patterns", "Fluctuating Sleep Timing", "Night-Time Disruptions" and "Lasting Effort Needed with Type Two Diabetes Mellitus". The subthemes reflected that many participants had consistent sleep schedules across the seven-day week, but that a desire to maintain a sense of normality, household routines, television schedules and socializing were associated with different sleep timing on weekends. Active disease monitoring and timed medication taking were not identified as important factors in shaping sleep timing. Nocturia, stress and rumination were identified as important factors linked to disrupted sleep. Sleep was not reported as an issue discussed during routine clinical care. CONCLUSION: Sleep timing in participants appears to be driven by interacting psychosocial and physiological factors, although active disease management does not emerge as a major influence on sleep schedules.

Metastatic HER2 lacrimal/salivary gland duct adenocarcinoma.

In this report, we present a case of a patient with a 30-year history of orbital asymmetry who presented with metastatic human epidermal growth factor receptor 2 (HER2) positive lacrimal/salivary gland ductal adenocarcinoma. The patient was treated with chemoradiotherapy and trastuzumab. Tumours of lacrimal gland origin are rare, and unfortunately can frequently present in late stage. There are no current guidelines on the optimal treatment of metastatic lacrimal gland tumours, in particular those with HER2 amplified malignancy. This case highlights a unique presentation of a rare disease, and the potential for targeted therapy.

Differences in Sleep Offset Timing between Weekdays and Weekends in 79,161 Adult Participants in the UK Biobank.

Variability in the timing of daily sleep is increasingly recognized as an important factor in sleep and general physical health. One potential driver of such daily variations in sleep timing is different work and social obligations during the "working week" and weekends. To investigate the nature of weekday/weekend differences in the timing of sleep offset, we examined actigraphy records of 79,161 adult participants in the UK Biobank who wore an actiwatch for 1 week. The time of sleep offset was found to be on average 36 min later on weekends than on weekdays, and when this difference was expressed as an absolute value (i.e., irrespective of sleep offset being either later or earlier on weekends), it was 63 min. Younger age, more socioeconomic disadvantage, currently being in employment, being a smoker, being male, being of non-white ethnicity and later chronotype were associated with greater differences in sleep offset between weekdays and weekend days. Greater differences in sleep offset timing were associated with age-independent small differences in cardiometabolic health indicators of BMI and diastolic blood pressure, but not HbA1c or systolic blood pressure. In a subset of participants with Type 2 Diabetes Mellitus, weekday/weekend sleep offset differences were associated weakly with BMI, systolic blood pressure and physical activity. Overall, this study demonstrates potentially substantive differences in sleep offset timings between weekdays and weekends in a large sample of UK adults, and that such differences may have public health implications.