Personalised future prescribing using pharmacogenomics: A resumé of a joint Royal College of Physicians / British Pharmacological Society working party report.

There is rapidly growing recognition of the important contribution of individually carried genetic factors to drug response variation (pharmacogenomics) for an increasingly wide range of drugs and of the resulting implications for healthcare across multiple specialisms. This concise overview of the March 2022 joint report of the Royal College of Physicians and the British Pharmacological Society on this topic outlines its coverage of aspects of scientific rationale (with examples), the so far largely unmet need for planned, systematic implementation and training within the UK NHS, and the key forward strategies required. They include a centrally funded, well defined developmental service design with implementation priorities, clinical decision support, clear clinical governance and ongoing research, public and patient engagement, and agreed, updated education and training packages.

Assessment and prevention of falls in older people--concise guidance.

Falls in later life are a major health issue, both in terms of their injurious consequences and their significance as a diagnostic marker. Cost-effective measures for their assessment and prevention are well documented but insufficiently implemented. This Concise Guideline comprises a distillation of recommendations for the assessment and prevention of falls in older people based on Clinical Guideline 161 (incorporating CG21) published by the National Institute of Health and Care Excellence (NICE) in 2013. The recommendations are intended to provide both generalists and specialists with an overview of practical strategies for clinical case and/or risk ascertainment and intervention, and for referral and service implementation across the primary-secondary care interface and within the hospital setting. Recommendations abstracted verbatim from the Guideline are highlighted. Explanatory or supporting comment is given as appropriate.

Prevention and management of hip fracture in older patients.

The average age at hip fracture is 83 for women and 84 for men, with about 80% of cases in women. The 30% mortality and 20% new institutionalisation rates at 12 months reflect the high prevalence of comorbidity and to some extent suboptimal management at the time of the fracture. With timely intervention and better clinical management many fractures can be prevented and when they do occur their human and economic costs can be greatly reduced. Fragility fractures occur in those with demonstrable osteoporosis or osteopaenia and/or risk factors. The goal of prevention is to identify and treat those at risk UK clinicians lack a single universally endorsed, decision support resource. The prudent strategy is to become familiar with all three available risk measures, introduce fracture risk assessment into routine practice, and allow clinical judgement to prevail in cases of doubt (perhaps, especially in very elderly people, more often in the direction of intervention). The classical signs after a fall by an older person, of severe pain, shortening and external rotation of the affected limb, and loss of mobility, should result in immediate and rapid transfer to hospital. It is not rare in the case of intracapsular fractures for mobility to be deceptively maintained on a moderately or minimally painful hip.

A randomized trial of effects of health risk appraisal combined with group sessions or home visits on preventive behaviors in older adults.

BACKGROUND: To explore effects of a health risk appraisal for older people (HRA-O) program with reinforcement, we conducted a randomized controlled trial in 21 general practices in Hamburg, Germany. METHODS: Overall, 2,580 older patients of 14 general practitioners trained in reinforcing recommendations related to HRA-O-identified risk factors were randomized into intervention (n = 878) and control (n = 1,702) groups. Patients (n = 746) of seven additional matched general practitioners who did not receive this training served as a comparison group. Patients allocated to the intervention group, and their general practitioners, received computer-tailored written recommendations, and patients were offered the choice between interdisciplinary group sessions (geriatrician, physiotherapist, social worker, and nutritionist) and home visits (nurse). RESULTS: Among the intervention group, 580 (66%) persons made use of personal reinforcement (group sessions: 503 [87%], home visits: 77 [13%]). At 1-year follow-up, persons in the intervention group had higher use of preventive services (eg, influenza vaccinations, adjusted odds ratio 1.7; 95% confidence interval 1.4-2.1) and more favorable health behavior (eg, high fruit/fiber intake, odds ratio 2.0; 95% confidence interval 1.6-2.6), as compared with controls. Comparisons between intervention and comparison group data revealed similar effects, suggesting that physician training alone had no effect. Subgroup analyses indicated favorable effects for HRA-O with personal reinforcement, but not for HRA-O without reinforcement. CONCLUSIONS: HRA-O combined with physician training and personal reinforcement had favorable effects on preventive care use and health behavior.

The impact of educational level on oral health-related quality of life in older people in London.

There are socioeconomic inequalities in oral health, but the relationship between education and oral health-related quality of life (OHRQoL) among older adults has not been adequately studied. This study assessed whether there is an educational gradient in OHRQoL among older people in London. We employed secondary analysis of baseline data (n = 1,090) from a randomized controlled trial of health-risk appraisal on community-dwelling non-disabled people 65 yr of age and older, registered with three group medical practices in suburban London. Multiple linear regressions were used to analyze the association between OHRQoL [measured using the Geriatric Oral Health Assessment Index (GOHAI)] and education, adjusted for age, gender, pension status, and denture wearing. Overall, 30.6% reported low levels of OHRQoL. Eating discomfort was the most frequent problem (24% reported 'often/always'), while concerns about appearance were also prevalent. Significant variations in OHRQoL existed between socioeconomic groups. In adjusted analyses, there was a clear education gradient in OHRQoL, with worse perceptions at each lower level of education. Low educational level has an independent negative impact on OHRQoL in older people, which is not explained by differences in income or in denture wearing between educational groups. Policies targeting lower educated groups should be complemented with whole-population strategies for the reduction of oral health inequalities.

The PRO-AGE study: an international randomised controlled study of health risk appraisal for older persons based in general practice.

BACKGROUND: This paper describes the study protocol, the recruitment, and base-line data for evaluating the success of randomisation of the PRO-AGE (PRevention in Older people-Assessment in GEneralists' practices) project. METHODS/DESIGN: A group of general practitioners (GPs) in London (U.K.), Hamburg (Germany) and Solothurn (Switzerland) were trained in risk identification, health promotion, and prevention in older people. Their non-disabled older patients were invited to participate in a randomised controlled study. Participants allocated to the intervention group were offered the Health Risk Appraisal for Older Persons (HRA-O) instrument with a site-specific method for reinforcement (London: physician reminders in electronic medical record; Hamburg: one group session or two preventive home visits; Solothurn: six-monthly preventive home visits over a two-year period). Participants allocated to the control group received usual care. At each site, an additional group of GPs did not receive the training, and their eligible patients were invited to participate in a concurrent comparison group. Primary outcomes are self-reported health behaviour and preventative care use at one-year follow-up. In Solothurn, an additional follow-up was conducted at two years. The number of older persons agreeing to participate (% of eligible persons) in the randomised controlled study was 2503 (66.0%) in London, 2580 (53.6%) in Hamburg, and 2284 (67.5%) in Solothurn. Base-line findings confirm that randomisation of participants was successful, with comparable characteristics between intervention and control groups. The number of persons (% of eligible) enrolled in the concurrent comparison group was 636 (48.8%) in London, 746 (35.7%) in Hamburg, and 1171 (63.0%) in Solothurn. DISCUSSION: PRO-AGE is the first large-scale randomised controlled trial of health risk appraisal for older people in Europe. Its results will inform about the effects of implementing HRA-O with different methods of reinforcement.

Development, feasibility and performance of a health risk appraisal questionnaire for older persons.

BACKGROUND: Health risk appraisal is a promising method for health promotion and prevention in older persons. The Health Risk Appraisal for the Elderly (HRA-E) developed in the U.S. has unique features but has not been tested outside the United States. METHODS: Based on the original HRA-E, we developed a scientifically updated and regionally adapted multilingual Health Risk Appraisal for Older Persons (HRA-O) instrument consisting of a self-administered questionnaire and software-generated feed-back reports. We evaluated the practicability and performance of the questionnaire in non-disabled community-dwelling older persons in London (U.K.) (N = 1090), Hamburg (Germany) (N = 804), and Solothurn (Switzerland) (N = 748) in a sub-sample of an international randomised controlled study. RESULTS: Over eighty percent of invited older persons returned the self-administered HRA-O questionnaire. Fair or poor self-perceived health status and older age were correlated with higher rates of non-return of the questionnaire. Older participants and those with lower educational levels reported more difficulty in completing the HRA-O questionnaire as compared to younger and higher educated persons. However, even among older participants and those with low educational level, more than 80% rated the questionnaire as easy to complete. Prevalence rates of risks for functional decline or problems were between 2% and 91% for the 19 HRA-O domains. Participants' intention to change health behaviour suggested that for some risk factors participants were in a pre-contemplation phase, having no short- or medium-term plans for change. Many participants perceived their health behaviour or preventative care uptake as optimal, despite indications of deficits according to the HRA-O based evaluation. CONCLUSION: The HRA-O questionnaire was highly accepted by a broad range of community-dwelling non-disabled persons. It identified a high number of risks and problems, and provided information on participants' intention to change health behaviour.

Lack of significant effects of methionine loading on endothelial function in elderly volunteers.

OBJECTIVE: To test the hypothesis that an acute increase in plasma homocysteine concentration (Hcy) produced by methionine loading is associated with an acute decrease in brachial artery blood flow measured by flow-mediated dilatation (FMD) using forearm plesthysmography. DESIGN: A double-blind, cross-over, placebo controlled design was used and FMD of the brachial artery, plasma Hcy, plasma methionine, total cholesterol, high density lipoprotein (HDL) cholesterol, low density lipoprotein (LDL) cholesterol, plasma triglyceride, oxidised LDL, apolipoproteins (Apo) A1 and B and C reactive protein (CRP) were measured between 12 and 20 hours after methionine loading or placebo. RESULTS: Between 12 and 20 hours, after a methionine loading test, acute hyperhomocysteinaemia had no significant effect on mean FMD compared to placebo (57.08+/-6.18ml/100ml/min versus 63.46+/-5.87ml/100ml/min, p<0.5). The mean age of the eight subjects was 71.5+/-6.9 years. Twelve hours after methionine, mean triglyceride concentration was significantly increased by 23.0% compared to placebo (1.51+/-0.47mmol/l versus 1.23+/-0.44mmol/l, p<0.02). CONCLUSION: In elderly volunteers, acute hyperhomocysteinaemia induced by methionine loading resulted in no significant late impairment of endothelial function although further investigation is recommended. Acute hyperhomocysteinaemia resulted in a significant increase in plasma triglyceride concentration.

The role of medical assessment and intervention in the prevention of falls.

Evidence that falls amongst older people can be prevented now requires researchers and policy makers to elucidate the most comprehensive and cost-effective approach to implementation. The syndrome of falls and fractures in later life reflects the combined age-associated influences of cumulative susceptibility to health problems and reduced adaptive reserve. The major contribution of health factors to falling has long been recognised clinically and has also emerged clearly in epidemiological studies of risk. A fall in an older adult, especially if recurrent, may be a key signal of unmet medical need and should accordingly trigger an in-depth diagnostic process and clinical intervention by an appropriately skilled physician. Although well-designed controlled studies specifying this approach as part of a multifactorial intervention are comparatively few, recent published trials have confirmed the anticipated substantial returns in fall prevention achieved for community-dwelling patients with a history of falling. Larger-scale studies are now required, and further research is needed to achieve effective prevention strategies in institutional care. Combined calcium and vitamin D may act via neuromuscular and skeletal mechanisms in fracture prevention. The requirement for medical assessment has now appropriately been incorporated into national and international guidelines.

Effects of folic acid supplementation on psychomotor performance and hemorheology in healthy elderly subjects.

Cognitive impairment is associated with increased blood concentrations of homocysteine and high blood viscosity. Previous studies have shown that vitamin B supplementation reduces homocysteine and enhances cognitive function in patients with mild dementia and low serum folic acid. However, whether folic acid enhances cognitive function in elderly subjects without dementia and normal serum folic acid is unknown. Twenty-four healthy elderly subjects (age 73.0+/-5.6 years, mean+/-S.D.) with normal serum folic acid (6.3+/-2.4 microg/l) and Mini Mental State Examination (MMSE) >27/30 were randomized to 4-week treatment with folic acid 5mg/day or placebo in a randomized, placebo-controlled, parallel-group study. Continuous Attention Test (CAT), Four-Choice Reaction Time (FCRT), Digit-Symbol Substitution (DSS), Scanning Memory Sets (SMS), and blood viscosity for different shear rates were measured before and after treatment. Folic acid supplementation induced a significant increase in serum folic acid levels (+13.8 versus +1.6 microg/l, p<0.001) and fall in homocysteine levels (-1.91 versus -0.41 micromol/l, p=0.05) compared to placebo. However, there was no significant change in CAT, FCRT, DSS, SMS, and blood viscosity between the two groups. Short-term folic acid supplementation does not enhance psychomotor performance or reduce blood viscosity in healthy elderly subjects with normal serum folic acid levels and preserved cognitive function.

Short-term oral folic acid supplementation enhances endothelial function in patients with type 2 diabetes.

BACKGROUND: Endothelial dysfunction and arterial stiffening are commonly observed in type 2 diabetes. These abnormalities might be secondary to increased plasma concentrations of homocysteine. We sought to determine whether oral folic acid supplementation, by lowering homocysteine levels, enhanced endothelial function and reduced arterial stiffness in type 2 diabetes. METHODS: Twenty-six type 2 diabetic patients (age 56.5 +/- 0.9 years, diabetes duration 5.5 +/- 0.6 years, means +/- SEM) with no history of cardiovascular disease received 5 mg/d of oral folic acid or placebo for 4 weeks in a double-blind, randomized controlled, parallel group trial. The following parameters were measured before and after treatment: 1) endothelial function (forearm arterial blood flow during local intra-arterial administration of endothelium-dependent [acetylcholine 1.5, 4.5, and 15 microg/min] and endothelium-independent [sodium nitroprusside 1, 2, and 4 microg/min] vasodilators); and 2) carotid-radial and carotid-femoral pulse wave velocity. RESULTS: Folic acid reduced plasma homocysteine concentrations and enhanced endothelium-dependent vasodilatation during each acetylcholine infusion rate (mean and 95% confidence interval post versus pretreatment differences in forearm arterial blood flow ratio between the infused and control arm +0.19 (0.03-0.35), P < .01; +0.39 (0.02-0.81), P < .05; and +0.40 (0.09-0.89), P < .05, respectively). Endothelium-independent vasodilatation and pulse wave velocity were not affected. No significant changes in forearm arterial blood flow and pulse wave velocity were observed in the placebo group. Multiple regression analysis showed that changes in folic acid, but not homocysteine, concentrations independently described changes in maximal endothelium-dependent vasodilatation. CONCLUSIONS: Short-term oral folic acid supplementation significantly enhances endothelial function in type 2 diabetic patients, independent of homocysteine lowering.

Vitamin D supplementation improves neuromuscular function in older people who fall.

BACKGROUND: vitamin D supplementation reduces the incidence of fractures in older adults. This may be partly mediated by effects of vitamin D on neuromuscular function. OBJECTIVE: to determine the effects of vitamin D supplementation on aspects of neuromuscular function known to be risk factors for falls and fractures. DESIGN: randomised, double-blind, placebo-controlled study. SETTING: falls clinic taking referrals from general practitioners and accident and emergency department. SUBJECTS: 139 ambulatory subjects (>/=65 years) with a history of falls and 25-hydroxyvitamin D (25OHD)

Effects of folic acid supplementation on inflammatory and thrombogenic markers in chronic smokers. A randomised controlled trial.

INTRODUCTION: Cigarette smoking may induce pro-inflammatory and pro-thrombotic changes. It is not known whether these abnormalities are caused at least partly by increased homocysteine levels. We investigated whether lowering homocysteine by folic acid supplementation might reduce the plasma concentration of inflammatory and thrombogenic markers in chronic smokers. MATERIAL AND METHODS: Twenty-four healthy cigarette smokers (age 37.8+/-2.5 years, mean+/-SEM) were randomly assigned to 4 weeks of folic acid 5 mg/day or placebo. The following parameters were measured before and after treatment: (1) markers of inflammation (C-reactive protein, CRP, and white cell count, WCC); (2) blood coagulation screen (Activated Partial Thromboplastin time Ratio, APTR, and International Normalized Ratio, INR); (3) pro-thrombotic markers (fibrinogen, factor VIII coagulant activity, VIII:C, von Willebrand factor, vWF, and D-dimer). RESULTS: Folic acid induced a significant reduction in homocysteine (10.8+/-0.6 vs. 8.2+/-0.5 micromol/l, p<0.001), plasma fibrinogen (3.15+/-0.14 vs. 2.87+/-0.14 g/l, p<0.05), and D-dimer (102+/-44 vs. 80+/-26 microg/l, p<0.05) concentrations. By contrast, no significant changes were observed in CRP (2.2+/-0.7 vs. 1.7+/-0.7 mg/l), WCC (7.2+/-0.5 vs. 6.8+/-0.5 10(9) cells/l), APTR (0.91+/-0.02 vs. 0.93+/-0.02), INR (0.92+/-0.01 vs. 0.91+/-0.01), vWF (103+/-8 vs. 102+/-9 U/dl), and VIII:C (120+/-8 vs. 107+/-8 U/dl) levels. Changes in folic acid plasma concentrations were significantly and negatively correlated with changes in fibrinogen (r=-0.48, p=0.01) but not with changes in D-dimer (r=-0.15, p=0.5) levels. Changes in plasma homocysteine concentrations did not correlate with changes in either fibrinogen or D-dimer. No significant changes in homocysteine, inflammatory and thrombogenic markers were observed in the placebo group. CONCLUSIONS: Short-term folic acid supplementation had no significant effects on inflammatory markers but induced a significant reduction in plasma fibrinogen and D-dimer concentrations in healthy chronic smokers. Thus, folic acid might have an anti-thrombotic effect in this high-risk group independent of the homocysteine lowering effect.

Influence of age on the enantiomeric disposition of ibuprofen in healthy volunteers.

AIMS: To determine the influence of age on the enantioselective disposition of ibuprofen in humans. METHODS: Healthy young (n = 16; aged 20-36 years) and elderly (n = 16; aged 66-84 years) volunteers were given a 400-mg oral dose of racemic ibuprofen, and blood and urine samples were collected for 24 h post drug administration. Serum concentrations, total and free, and urinary excretion of both enantiomers of ibuprofen together with the urinary excretion of the stereoisomers of the two major metabolites of the drug, both free and conjugated, were determined by high-performance liquid chromatography. RESULTS: Ageing had little effect on the distribution and metabolism of R-ibuprofen, unbound clearance of the R-enantiomer via inversion being approximately two-fold that via noninversion mechanisms in both age groups. In contrast, the free fraction of S-ibuprofen was significantly greater [33%; young 0.48 +/- 0.10%; elderly 0.64 +/- 0.20%] mean difference -0.16; 95% confidence interval (CI) -0.05, -0.27; P < 0.01; and the unbound clearance of the drug enantiomer was significantly lower (28%; young 15.9 +/- 2.2 l min-1; elderly 11.5 +/- 4.1 l min-1; mean difference 4.4; 95% CI 2.12, 6.68; P < 0.001) in the elderly. The metabolite formation clearances of S-ibuprofen via glucuronidation, and oxidation at the 2- and 3- positions of the isobutyl side chain decreased by 24, 28 and 30%, respectively, in the elderly compared with the young, the differences between the two age groups being significant in each case (P < 0.05). CONCLUSIONS: Following administration of racemic ibuprofen age-associated stereoselective alterations in drug disposition have been observed, with the elderly having increased free concentrations and lower unbound clearance of the S-enantiomer in comparison with the young. In contrast, the handling of the R-enantiomer is essentially unaltered with age. The results of this study indicate that the elderly have an increased exposure to the active ibuprofen enantiomer and thus some caution may be required when using this drug in this age group.

Paradoxical vasodilation during lower body negative pressure in patients with vasodepressor carotid sinus syndrome.

OBJECTIVES: To elucidate the pathophysiological mechanism of the vasodepressor form (VD) of carotid sinus syndrome (CSS) by maneuvers designed to induce generalized sympathetic activation after baroreceptor unloading (lower body negative pressure, LBNP) or direct peripheral adrenoreceptor stimulation via local administration of norepinephrine (NA). DESIGN: Subjects were identified with VD of CSS through diagnostic testing. SETTING: Research laboratory. PARTICIPANTS: Eleven young controls (YC) (mean age +/- standard error of mean = 22.8 +/- 0.7), eight elderly controls (EC) (72.6 +/- 0.6), and eight elderly patients with VD (78.7 +/- 1.7). MEASUREMENTS: Forearm arterial blood flow (FABF) was measured in the left and right arms by venous occlusion plethysmography. Measurements were performed during baseline conditions, LBNP (-20 mmHg), and intra-arterial NA infusion in the left brachial artery at three progressively increasing rates (60, 120, and 240 pmol/min). RESULTS: During LBNP, FABF significantly decreased in YC (baseline 3.61 +/- 0.30 vs -20 mmHg 2.96 +/- 0.24 mL/100 g/min, P =.030) and EC (4.05 +/- 0.74 vs 3.69 +/- 0.65 mL/100 g/min, P =.033) but increased in elderly patients with VD (3.65 +/- 0.60 vs 4.54 +/- 0.80 mL/100 g/min, P =.020). During NA infusion, a significant forearm vasoconstriction occurred in YC (FABF left:right ratio 1.00 +/- 0.05 at baseline; 0.81 +/- 0.08 at 60 pmol/min, P =.034; 0.81 +/- 0.05 at 120 pmol/min, P <.001; 0.72 +/- 0.04 at 240 pmol/min, P <.001), whereas no significant FABF changes were observed in EC (1.04 +/- 0.06; 0.96 +/- 0.07, P =.655; 0.89 +/- 0.10, P =.401; 0.94 +/- 0.10, P =.590) or elderly patients with VD (1.04 +/- 0.06; 1.16 +/-0.10, P =.117; 1.04 +/- 0.08, P =.602; 1.11 +/- 0.10, P =.305). CONCLUSION: VD of CSS is associated with a paradoxical vasodilatation during LBNP and an impairment of peripheral alpha-adrenergic responsiveness, which may be age-related.