Clive Bowman

Genome-wide approaches to identify pharmacogenetic contributions to adverse drug reactions.

Adverse drug reactions (ADRs) have a major impact on patients, physicians, health care providers, regulatory agencies and pharmaceutical companies. Identifying the genetic contributions to ADR risk may lead to a better understanding of the underlying mechanisms, identification of patients at risk and a decrease in the number of events. Technological advances have made the routine monitoring and investigation of the genetic basis of ADRs during clinical trials possible. We demonstrate through simulation that genome-wide genotyping, coupled with the use of clinically matched or population controls, can yield sufficient statistical power to permit the identification of strong genetic predictors of ADR risk in a prospective manner with modest numbers of ADR cases. The results of a 500 000 single nucleotide polymorphism analysis of abacavir-associated hypersensitivity reaction suggest that the known HLA-B gene region could be identified with as few as 15 cases and 200 population controls in a sequential analysis.

Investigation into the multidimensional genetic basis of drug-induced Stevens–Johnson syndrome and toxic epidermal necrolysis

OBJECTIVE Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare severe blistering skin diseases, which are mainly caused by drugs. The two idiosyncratic conditions are distinguished on the basis of the degree of blistering, possibly representing diseases at different ends of the same spectrum. A genetic predisposition has been postulated. METHOD We have retrospectively identified a heterogeneous group of patients with SJS and TEN (n = 73 cases, 141 matched controls) induced by a number of marketed drugs and evaluated effector candidate genetic predisposition. We have used a multivariate genetic analysis method for the first time to handle the heterogeneity of clinical presentation, drug etiology, ethnicity and gender in these adverse events. RESULTS Our results show that predisposition varied according to ethnicity. There was a correlation for SJS with HLA-B*44, DRB1*07 and with the MHC ancestral 57.1 haplotype (and its constituents) in subjects who self-reported as Caucasians, which did not differ with gender. The HLA-DRB and -DRQ genetic predisposition to SJS seemed to be distinct from that of TEN, but further work is needed for both conditions to identify the causal variants. No conclusion concerning correlations with different drugs could be made because of small numbers in each drug group. CONCLUSION This study stresses the importance of accurate clinical phenotyping, exemplifies a novel analysis method to dissect complicated samples and calls for collaborative prospective studies.

TNF, LTA, HSPA1L and HLA‑DR gene polymorphisms in HIV-positive patients with hypersensitivity to cotrimoxazole

AIMS Sulfamethoxazole in combination with trimethoprim (cotrimoxazole) is used for prophylaxis and treatment of several opportunistic infections in HIV-infected patients. It is associated with a high incidence of hypersensitivity reactions, which is thought to have an immune basis. Genetic polymorphisms in MHC are known to predispose to hypersensitivity reactions to a structurally diverse group of drugs in HIV-positive patients. The aim of the study was to determine whether functional polymorphisms in TNF, LTA, HSPA1L and HLA-DRB1 genes influence the risk of cotrimoxazole hypersensitivity in HIV-infected patients. METHODS We genotyped 136 HIV-positive patients with (n = 53) and without (n = 83) cotrimoxazole hypersensitivity using a combination of PCR-based techniques, including PCR-restriction fragment length polymorphisms, PCR-sequence specific oligonucleotides and real-time PCR. Genotypes and the haplotype frequencies were analyzed using the chi(2) test in the Haploview and CLUMP programs. RESULTS No statistically significant difference in SNP or haplotype frequencies were found in HIV-infected sulfamethoxazole hypersensitive patients compared with controls. CONCLUSION Our data show that MHC polymorphisms are not major predisposing factors for cotrimoxazole hypersensitivity, although we cannot exclude a minor contribution. An environmental factor (i.e., HIV infection) seems to predominate over any of the genetic factors so far investigated in increasing the risk of cotrimoxazole hypersensitivity.

Effective health care for older people living and dying in care homes: A realist review

BackgroundCare home residents in England have variable access to health care services. There is currently no coherent policy or consensus about the best arrangements to meet these needs. The purpose of this review was to explore the evidence for how different service delivery models for care home residents support and/or improve wellbeing and health-related outcomes in older people living and dying in care homes.MethodsWe conceptualised models of health care provision to care homes as complex interventions. We used a realist review approach to develop a preliminary understanding of what supported good health care provision to care homes. We completed a scoping of the literature and interviewed National Health Service and Local Authority commissioners, providers of services to care homes, representatives from the Regulator, care home managers, residents and their families. We used these data to develop theoretical propositions to be tested in the literature to explain why an intervention may be effective in some situations and not others. We searched electronic databases and related grey literature. Finally the findings were reviewed with an external advisory group.ResultsStrategies that support and sustain relational working between care home staff and visiting health care professionals explained the observed differences in how health care interventions were accepted and embedded into care home practice. Actions that encouraged visiting health care professionals and care home staff jointly to identify, plan and implement care home appropriate protocols for care, when supported by ongoing facilitation from visiting clinicians, were important. Contextual factors such as financial incentives or sanctions, agreed protocols, clinical expertise and structured approaches to assessment and care planning could support relational working to occur, but of themselves appeared insufficient to achieve change.ConclusionHow relational working is structured between health and care home staff is key to whether health service interventions achieve health related outcomes for residents and their respective organisations. The belief that either paying clinicians to do more in care homes and/or investing in training of care home staff is sufficient for better outcomes was not supported.

Textbook of Men's Health

From the title one might expect a distillation from popular magazines devoted to male fitness and narcissism. In fact the book emanates from the International Society for the Study of the Aging Male. I received it with curiosity mixed with guilt—the former because I wondered what a specific textbook could offer over and above established textbooks of medicine; the latter the guilt of one who has lapsed. Anticipation was quickly overtaken by the controlled panic of clinical self-doubt: could the seemingly all-pervasive presence of androgenic matters be pointing to a major black hole in a ‘mature’ clinical repertoire? Though I can claim my fair share of clinical coups in older men complaining vaguely of being tired all the time—coeliac disease, myasthenia gravis, and a meningioma, to name just a few—never have I diagnosed an ‘andropause’. Discreet questioning of unequivocally able colleagues suggests I am not alone. Androgens clearly have interesting roles, but the multiple accounts of androgenic pathophysiology scattered throughout this book are cumulatively unconvincing as well as repetitive. To judge from these accounts, a person answering a multiple-choice question on the symptoms of androgen deficiency would best go for the option ‘all of the above’. There seems to be no consensus on reference values for adrenal androgens. The question posed, ‘Does visceral adiposity induce low levels of testosterone, or do low levels of testosterone induce visceral adiposity?’ simply led me to wonder idly about the role of lager and other male secular comforts. As to be expected in a multiauthor book, some of the contributors provide good well-rounded accounts—for example, the substantial chapters on the genitourinary system and the concise and well written account of hair disorders. This is not, however, a comprehensive text, and matters such as Parkinsons disease, accidents, suicide, stroke, amputation and rehabilitation are notably absent, contrary to the medical experience of ageing men. The final chapter, on hormone treatments and preventive strategies, is overwhelmingly and unacceptably dominated by androgens. 69 references largely relate to androgens, yet a discussion of melatonin, which suggests that ‘Insomnia observed in some elderly people can be partially restored by administering Melatonin’, is based on trials that are not referenced. The prescribing advice does not feel robust—for UK readers, not NICE at all. A textbook addressing a defined field such as this should provide a balanced account and the editors should condense the material, where possible, to provide a coherent narrative. I cannot recommend this work, but for a second opinion I showed it to two third-year medical students. After dipping into and out of it over several lazy summer days they were more positive, suggesting that they would use it if it were in their library; so it may have a place. I am sure androgens themselves have a place in a text on this subject, but the promised future editions should corral them into a single coherent account and widen the horizons.

Provision of NHS generalist and specialist services to care homes in England: review of surveys

BACKGROUND The number of beds in care homes (with and without nurses) in the United Kingdom is three times greater than the number of beds in National Health Service (NHS) hospitals. Care homes are predominantly owned by a range of commercial, not-for-profit or charitable providers and their residents have high levels of disability, frailty and co-morbidity. NHS support for care home residents is very variable, and it is unclear what models of clinical support work and are cost-effective. OBJECTIVES To critically evaluate how the NHS works with care homes. METHODS A review of surveys of NHS services provided to care homes that had been completed since 2008. It included published national surveys, local surveys commissioned by Primary Care organisations, studies from charities and academic centres, grey literature identified across the nine government regions, and information from care home, primary care and other research networks. Data extraction captured forms of NHS service provision for care homes in England in terms of frequency, location, focus and purpose. RESULTS Five surveys focused primarily on general practitioner services, and 10 on specialist services to care home. Working relationships between the NHS and care homes lack structure and purpose and have generally evolved locally. There are wide variations in provision of both generalist and specialist healthcare services to care homes. Larger care home chains may take a systematic approach to both organising access to NHS generalist and specialist services, and to supplementing gaps with in-house provision. Access to dental care for care home residents appears to be particularly deficient. CONCLUSIONS Historical differences in innovation and provision of NHS services, the complexities of collaborating across different sectors (private and public, health and social care, general and mental health), and variable levels of organisation of care homes, all lead to persistent and embedded inequity in the distribution of NHS resources to this population. Clinical commissioners seeking to improve the quality of care of care home residents need to consider how best to provide fair access to health care for older people living in a care home, and to establish a specification for service delivery to this vulnerable population.

Relationships, expertise, incentives, and governance: Supporting care home residents' access to health care: An interview study from England

Objectives To explore what commissioners of care, regulators, providers, and care home residents in England identify as the key mechanisms or components of different service delivery models that support the provision of National Health Service (NHS) provision to independent care homes. Methods Qualitative, semistructured interviews with a purposive sample of people with direct experience of commissioning, providing, and regulating health care provision in care homes and care home residents. Data from interviews were augmented by a secondary analysis of previous interviews with care home residents on their personal experience of and priorities for access to health care. Analysis was framed by the assumptions of realist evaluation and drew on the constant comparative method to identify key themes about what is required to achieve quality health care provision to care homes and resident health. Results Participants identified 3 overlapping approaches to the provision of NHS that they believed supported access to health care for older people in care homes: (1) Investment in relational working that fostered continuity and shared learning between visiting NHS staff and care home staff, (2) the provision of age-appropriate clinical services, and (3) governance arrangements that used contractual and financial incentives to specify a minimum service that care homes should receive. Conclusion The 3 approaches, and how they were typified as working, provide a rich picture of the stakeholder perspectives and the underlying assumptions about how service delivery models should work with care homes. The findings inform how evidence on effective working in care homes will be interrogated to identify how different approaches, or specifically key elements of those approaches, achieve different health-related outcomes in different situations for residents and associated health and social care organizations.

Formative Care: Defining the purpose and clinical practice of care for the frail

The emerging population of older people with chronic, progressive degenerative diseases pose the greatest challenge to the sustainability of health and care systems but services are not well developed for their needs1,2 and robust metrics of experience lacking. Modern Medicine generally can be described in terms of prevention, diagnosis and the evidenced treatment of acute and long-term conditions. Additionally, and particularly, for older people needs assessment, rehabilitation, palliative and end of life care are well established. These clinical domains are broadly mirrored in social care where prevention, personalisation, enablement, empowerment and risk management are commonly cited. The early phase of Geriatric Medicine highlighted the importance of Comprehensive Geriatric Assessment, treatment and rehabilitation in reducing care needs3 and the improvement of living conditions and general support.4 Collectively, these have successfully limited avoidable dependency. In recent years, development has focused on improving end of life care. However, ageing populations feature a growing number of older dependent people who are increasingly unresponsive to traditional treatment(s) but for whom dying and death is not imminently anticipated. This emerging dependent population is increasingly recognized5 as is the complexity of managing multiple morbidities.6 However, there is little coherence to the purpose of medicine for this population in spite of frequent public, professional and political concerns with common themes of dignity, quality of life and affordability.7,8 The continued major failures of care9 and inadequate clarity over life status10 or monitoring measures to assess experience11 all point to a need for new thinking in this ‘clinical space’.

Geriatric care in the United Kingdom: aligning services to needs

# Geriatric care in the United Kingdom: aligning services to needs {#article-title-2} Current provision and funding of health and social care for older people in the United Kingdom are undermined by a structural and operational misalignment of primary healthcare teams, acute hospital trusts, community trusts, and social services. The problem has been compounded by the fact that funding originates from at least three sources: the NHS, local social services departments, and personal or insured means. The inevitable result is obfuscation of responsibilities. The recent report from the Royal Commission on Long Term Care, With Respect To Old Age ,1 recommends the establishment of a national care commission to monitor trends, costs, accountability, and the interests of the consumer and to set national benchmarks. This builds logically on policy trends signalled in the government discussion paper Partnership in Action and Modernising Social Services , which suggest a national regulatory system and standards.2 3 In this article we outline a possible solution that integrates and aligns health and personal care for elderly people in a practical and incremental manner. To put our strategic proposals in a contemporary perspective we briefly outline some present issues. #### Summary points Health care tends to focus on acute problems at the expense of managing and preventing exacerbations of chronic illness. Long term care of elderly people has been shifted from hospital to residential homes. A partnership is proposed including general practitioners, geriatricians, and social support staff for care of frail elderly people. Partnership would be encouraged to and responsible for maintaining and improving the health of frail people rather than fire fight acute illness. Planned, supported, and funded care by general practitioners may improve the health of care home residents and avoid episodes of expensive care. The locus of long term care has shifted from hospital long stay wards directed by geriatricians to privately operated community nursing and residential …

Antipsychotic prescribing in care homes before and after launch of a national dementia strategy: an observational study in English institutions over a 4-year period

Objectives To assess associations between the launch of the National Dementia Strategy (NDS) and antipsychotic prescribing in long-term residential care (LTC) in England. Setting and participants Retrospective analysis of prescribing patterns in 616 LTC institutions (31 619 residents) following launch of the NDS, using information from electronic medicines management system. Primary and secondary outcome measures Antipsychotic prescribing point prevalence (PP) for all residents in a cross section of LTC settings over a 4-year period following NDS launch. Secondary outcomes included dosages, length of treatment and use of recommended second-generation antipsychotics (SGAs) versus first-generation antipsychotics (FGAs). Associations between facility-level PP values and institutional characteristics, resident demographics were explored. Variations across geographical areas examined. Prescription net ingredient costs calculated. Results No statistically significant difference was observed in overall prescribing rates over the 4-year period (Kolmogorov-Smirnov (KS) test p=0.60), and there was no significant shift towards newer SGAs (KS test p=0.32). Dosages were above the maximum indicated in only 1.3% of cases, but duration of prescribing was excessive in 69.7% of cases. Care homes in the highest prescribing quintile were more likely to be located in a deprived area (rate ratio (Q5/Q1) RR=5.89, 95% CI 4.35 to 7.99), registered for dementia (RR=3.38, 95% CI 3.06 to 3.73) and those in the lowest quintile were more likely to be served by a single general practitioner (GP) practice (RR=0.48; 95% CI 0.37 to 0.63); p<0.001 all. A sixfold variation in PP levels was observed between geographical areas. The average annual expenditure on antipsychotics was £65.6 per person resident (2012 prices). Conclusions The NDS in England was not associated with reduced PP levels or the types of antipsychotic prescribing in care homes. Further research is needed to explore why. Clear standards specifying recommended agents, dosages and length of treatment, together with routine monitoring and greater accountability for antipsychotic prescribing, may be required.