The DietCompLyf study: A prospective cohort study of breast cancer survival and phytoestrogen consumption

DietCompLyf is a multi-centre prospective study designed to investigate associations between phytoestrogens - naturally occurring plant compounds with oestrogenic properties - and other diet and lifestyle factors with breast cancer recurrence and survival. 3159 women with grades I-III breast cancer were recruited 9-15 months post-diagnosis from 56 UK hospitals. Detailed information on clinico-pathological, diet, lifestyle and quality of life is collected annually up to 5 years. Biological samples have also been collected as a resource for subsequent evaluation. The characteristics of the patients and associations between pre-diagnosis intake of phytoestrogens (isoflavones and lignans; assessed using the EPIC-Norfolk UK 130 question food frequency questionnaire) and breast cancer (i) risk factors and (ii) prognostic factors are described for 1797 women who had complete data for all covariates and phytoestrogens of interest. Isoflavone intakes were higher in the patients who were younger at diagnosis, in the non-smokers, those who had breast-fed and those who took supplements. Lignan intakes were higher in patients with a higher age at diagnosis, in ex-smokers, those who had breast-fed, who took supplements, had a lower BMI at diagnosis, lower age at menarche and were nulliparous. No significant associations between pre-diagnosis phytoestrogen intake and factors associated with improved breast cancer prognosis were observed. The potential for further exploration of the relationship between phytoestrogens and breast cancer recurrence and survival, and for the establishment of evidence to improve dietary and lifestyle advice offered to patients following breast cancer diagnosis using DietCompLyf data is discussed.

The difficult-to-treat, therapy-resistant cough: Why are current cough treatments not working and what can we do?

Cough can persist despite exhaustive diagnostic and therapeutic effort and has been termed 'idiopathic' or 'unexplained' but perhaps 'difficult to treat' cough is a more appropriate description. In this article the reasons for poor treatment response are discussed. These include a lack of physician fidelity to management guidelines, patient non-adherence and the lack of effective medicines. A number of randomized controlled trials have been undertaken including low dose opiate therapy, the use of a speech pathology intervention, oral antibiotics and antidepressants. The success or otherwise of such interventions will be discussed. A number of approaches to deal with the problem of 'difficult to treat cough' will be considered.

An exploration of nursing home managers' knowledge of and attitudes towards the management of pain in residents with dementia

Background The aims of this study were to explore the knowledge, attitudes and beliefs that nursing home managers hold with regard to the assessment and management of pain in residents with dementia and to determine how these may be affected by the demographic characteristics of the respondents.

Methods A questionnaire comprising six sections was mailed, on two occasions during March and April 2010, to 244 nursing home managers in Northern Ireland (representing 96% of the nursing homes in Northern Ireland).

Results The response rate was 39%. Nearly all respondents (96%) provided care to residents with dementia, yet only 60% of managers claimed to use pain treatment guidelines within their nursing home. Respondents demonstrated good knowledge about pain in residents with dementia and acknowledged the difficulties surrounding accurate pain assessment. Nursing home managers were uncertain about how to manage pain in residents with dementia, demonstrating similar concerns about the use of opioid analgesics to those reported in previous studies about pain in older people. Managers who had received recent training (p = 0.044) were less likely to have concerns about the use of opioid analgesia than those who had not received training. Respondents' beliefs about painkillers were largely ambivalent and were influenced by the country in which they had received their nursing education.

Conclusions The study has revealed that accurate pain assessment, training of nursing staff and a standardised approach to pain management (the use of pain management guidelines) within nursing homes all have a significant part to play in the successful management of pain in residents with dementia. Copyright (c) 2012 John Wiley & Sons, Ltd.

Carotenoids and health in older people

As the proportion of older people increases, so will chronic disease incidence and the proportion of the population living with disability. Therefore, new approaches to maintain health for as long as possible in this age group are required. Carotenoids are a group of polyphenolic compounds found predominantly in fruit and vegetables that have been proposed to have anti-inflammatory and antioxidant effects. Such properties may impact on the risk diseases which predominate in older people, and also ageing-related physiological changes. Working out the effect of carotenoid intake versus fruit and vegetable intake is difficult, and the strong correlation between individual carotenoid intakes also complicates any attempt to examine individual carotenoid health effects. Similarly, research to determine whether carotenoids consumed as supplements have similar benefits to increased dietary intake through whole foods, is still required. However, reviewing the recent evidence suggests that carotenoid intake and status are relatively consistently associated with reduced CVD risk, although β-carotene supplementation does not reduce CVD risk and increases lung cancer risk. Increased lycopene intake may reduce prostate cancer progression, with a potential role for carotenoids at other cancer sites. Lutein and zeaxanthin have a plausible role in the maintenance of eye health, whilst an association between carotenoid intake and cognitive and physical health appears possible, although research is limited to date. Given this accruing evidence base to support a specific role for certain carotenoids and ageing, current dietary advice to consume a diet rich in fruit and vegetables would appear prudent, and efforts maintained to encourage increased intake.

An Observational Study of Blood Concentrations and Kinetics of Methyl- and Propyl-Parabens in Neonates

Purpose: Systemic exposure to parabens in the neonatal population, in particular propyl-parabens (PPB), remains a concern. Blood concentrations and kinetics of methyl-parabens (MPB) and PPB were therefore determined in neonates receiving medicines containing these excipients.

Methods: A multi-centre, non-interventional, observational study of excipient-kinetics in neonates. ‘Dried Blood Spot’ samples were collected opportunistically at the same time as routine samples and the observations modelled using a non-linear mixed effects approach.

Results: A total of 841 blood MPB and PPB concentration data were available for evaluation from 181 pre- and term-neonates. Quantifiable blood concentrations of MPB and PPB were observed in 99% and 49% of patients, and 55% and 25% of all concentrations were above limit of detection (10 ng/ml), respectively. Only MPB data was amenable to modelling. Oral bioavailability was influenced by type of formulation and disposition was best described by a two compartment model with clearance (CL) influenced by post natal age (PNA); CL_{PNA<21 days} 0.57 versus CL_PNA>21days 0.88 L/h.

Conclusions: Daily repeated administration of parabens containing medicines can result in prolonged systemic exposure to the parent compound in neonates. Animal toxicology studies of PPB that specifically address the neonatal period are required before a permitted daily exposure for this age group can be established.

Establishing a nurse practitioner collaborative: evolution, development, and outcomes

The first Australian palliative care nurse practitioner (NP) was endorsed in 2003. In 2009 the Victoria Department of Health funded the development of the Victorian Palliative Care Nurse Practitioner Collaborative (VPCNPC). Its aim was to promote the NP role, develop resources, and provide education and mentorship to NPs, nurse practitioner candidates (NPCs), and health service managers. Four key objectives were developed: identify the demographic profile of palliative care NPCs in Victoria; develop an education curriculum and practical resources to support the training and education of palliative care NPCs and NPs; provide mentorship to NPs, NPCs, and service managers; and ensure effective communication with all key stakeholders. An NPC survey was also conducted to explore NPC demographics, models of care, the hours of study required for the role, the mentoring process, and education needs. This paper reports on the establishment of the VPCNPC, the steps taken to achieve its objectives, and the results of the survey. The NP role in palliative care in Australia continues to evolve, and the VPCNPC provides a structure and resources to clearly articulate the benefits of the role to nursing and clinical services. The advanced clinical practice role of the nurse practitioner (NP) has been well established in North America for several decades and across a range of specialties (Ryan-Woolley et al, 2007; Poghosyan et al, 2012). The NP role in Australia and the UK is a relatively new initiative that commenced in the early 2000s (Gardner et al, 2009). There are over 1000 NPs across all states and territories of Australia, of whom approximately 130 work in the state of Victoria (Victorian Government Health Information, 2012). Australian NPs work across a range of specialties, including palliative, emergency, older person, renal, cardiac, respiratory, and mental health care. There has been increasing focus nationally and internationally on developing academic programmes specifically for nurses working toward NP status (Gardner et al, 2006). There has been less emphasis on identifying the comprehensive clinical support requirements for NPs and NP candidates (NPCs) to ensure they meet all registration requirements to achieve and/or maintain endorsement, or on articulating the ongoing requirements for NPs once endorsed. Historically in Australia there has been a lack of clarity and limited published evidence on the benefits of the NP role for patients, carers, and health services (Quaglietti et al, 2004; Gardner and Gardner, 2005; Bookbinder et al, 2011; Dyar et al, 2012). An NP is considered to be at the apex of clinical nursing practice. The NP role typically entails comprehensively assessing and managing patients, prescribing medicines, making direct referrals to other specialists and services, and ordering diagnostic investigations (Australian Nursing and Midwifery Council, 2009). All NPs in Australia are required to meet the following generic criteria: be a registered nurse, have completed a Nursing and Midwifery Board of Australia approved postgraduate university Master's (nurse practitioner) degree programme, and be able to demonstrate a minimum of 3 years' experience in an advanced practice role (Nursing and Midwifery Board of Australia, 2011). An NPC in Victoria is a registered nurse employed by a service or organisation to work toward meeting the academic and clinical requirements for national endorsement as an NP. During the period of candidacy, which is of variable duration, NPCs consolidate their competence to work at the advanced practice level of an NP. The candidacy period is a process of learning the new role while engaging with mentors (medical and nursing) and accessing other learning opportunities both within and outside one's organisation to meet the educational requirements. Integral to the NP role is the development of a model of care that is responsive to identified service delivery gaps that can be addressed by the skills, knowledge, and expertise of an NP. These are unique to each individual service. The practice of an Australian NP is guided by national standards (Nursing and Midwifery Board of Australia 2014). It is defined by four overarching standards: clinical, education, research, and leadership. Following the initial endorsement of four Victorian palliative care NPs in 2005, there was a lull in recruitment. The Victoria Department of Health (DH) recognised the potential benefits of NPs for health services, and in 2008 it provided funding for Victorian public health services to scope palliative care NP models of care that could enhance service delivery and patient outcomes. The scoping strategy was effective and led to the appointment of 16 palliative care nurses to NPC positions over the ensuing 3 years. The NPCs work across a broad range of care settings, including inpatient, community, and outpatient in metropolitan, regional, and rural areas of Victoria. At the same time, the DH also funded the Centre for Palliative Care to establish the Victorian Palliative Care Nurse Practitioner Collaborative (VPCNPC) to support the NPs and NPCs. The Centre is a state-wide service that is part of St Vincent's Hospital Melbourne and a collaborative Centre of the University of Melbourne. Its primary function is to provide training and conduct research in palliative care. The purpose of the VPCNPC was to provide support and mentorship and develop resources targeted at palliative care NPs, NPCs, and health service managers. Membership of the VPCNPC is open to all NPs, NPCs, health service managers, and nurses interested in the NP role. The aim of this paper is to describe the development of the VPCNPC, its actions, and the outcomes of these actions.

Plants Fagonia cretica L. and Hedera nepalensis K. Koch contain natural compounds with potent dipeptidyl peptidase-4 (DPP-4) inhibitory activity

Ethnopharmacological relevance
The two plants investigated here (Fagonia cretica L. and Hedera nepalensis K. Koch) have been previously reported as natural folk medicines for the treatment of diabetes but until now no scientific investigation of potential anti-diabetic effects has been reported. 

Materials and methods
In vitro inhibitory effect of the two tested plants and their five isolated compounds on the dipeptidyl peptidase 4 (DPP-4) was studied for the assessment of anti-diabetic activity. 

Results
A crude extract of Fagonia cretica possessed good inhibitory activity (IC₅₀value: 38.1 μg/ml) which was also present in its n-hexane (FCN), ethyl acetate (FCE) or aqueous (FCA) fractions. A crude extract of Hedera nepalensis (HNC) possessed even higher inhibitory activity (IC₅₀value: 17.2 μg/ml) and this activity was largely retained when further fractionated in either ethyl acetate (HNE; IC₅₀: 34.4 μg/ml) or n-hexane (HNN; 34.2 μg/ml). Bioactivity guided isolation led to the identification of four known compounds (isolated for the first time) from Fagonia cretica: quinovic acid (1), quinovic acid-3β-O-β-d-glycopyranoside (2), quinovic acid-3β-O-β-d-glucopyranosyl-(28→1)-β-d-glucopyranosyl ester (3), and stigmasterol (4) all of which inhibited DPP-4 activity (IC₅₀: 30.7, 57.9, 23.5 and >100 μM, respectively). The fifth DPP-4 inhibitor, the triterpenoid lupeol (5) was identified in Hedera nepalensis (IC₅₀: 31.6 μM). 

Conclusion
The experimental study revealed that Fagonia cretica and Hedera nepalensis contain compounds with significant DPP-4 inhibitory activity which should be further investigated for their anti-diabetic potential.

Aspirin and folic acid for the prevention of recurrent colorectal adenomas

BACKGROUND & AIMS: Although observational studies have found regular aspirin use to be associated with a reduced risk of colorectal neoplasia, results from randomized trials using aspirin have been inconsistent. Dietary folate intake also has been found to be associated with a reduced risk of colorectal neoplasms in observational studies.

METHODS: A multicenter, randomized, double-blind trial of aspirin (300 mg/day) and folate supplements (0.5 mg/day) to prevent colorectal adenoma recurrence was performed using a 2 x 2 factorial design. All patients had an adenoma (>/=0.5 cm) removed in the 6 months before recruitment and were followed-up at 4-month intervals with a second colonoscopy after approximately 3 years. The primary outcome measure was a colorectal adenoma diagnosed after baseline.

RESULTS: A total of 945 patients were recruited into the study, of whom 853 (90.3%) underwent a second colonoscopy. In total, 99 (22.8%) of 434 patients receiving aspirin had a recurrent adenoma compared with 121 (28.9%) of 419 patients receiving placebo (relative risk, 0.79; 95% confidence interval [CI], 0.63-0.99). A total of 104 patients developed an advanced colorectal adenoma; 41 (9.4%) of these were in the aspirin group and 63 (15.0%) were in the placebo group (relative risk, 0.63; 95% CI, 0.43-0.91). Folate supplementation was found to have no effect on adenoma recurrence (relative risk, 1.07; 95% CI, 0.85-1.34).

CONCLUSIONS: Aspirin (300 mg/day) but not folate (0.5 mg/day) use was found to reduce the risk of colorectal adenoma recurrence, with evidence that aspirin could have a significant role in preventing the development of advanced lesions.

Hydrophilic Interaction Ultra-High Performance Liquid Chromatography Coupled with Triple-Quadrupole Mass Spectrometry for Determination of Nucleosides and Nucleobases in Animal Horns

Traditional Chinese Medicines (TCMs) derived from animal horns are one of the most important types of Chinese medicine. In the present study, a fast and sensitive analytical method was established for qualitative and quantitative determination of 14 nucleosides and nucleobases in animal horns using hydrophilic interaction ultra-high performance liquid chromatography coupled with triple-quadruple tandem mass spectrometry (HILIC-UPLC-QQQ-MS/MS) in selective reaction monitoring (SRM) mode. The method was optimized and validated, and showed good linearity, precision, repeatability, and accuracy. The method was successfully used to determine contents of the 14 nucleosides and nucleobases in 25 animal horn samples. Hierarchical clustering analysis (HCA) and principal component analysis (PCA) were performed and the 25 samples were thereby divided into two groups, which agreed with taxonomy. The method may enable quick and effective search of substitutes for precious horns.

Parents’ and young people’s involvement in designing a trial of ventilator weaning

Consulting with users is considered best practice and is highly recommended in designing new trials. As part of our feasibility work, we undertook a consultation exercise with parents, ex-patients and young people prior to designing a trial of protocol-based ventilator weaning. Our aims were to (1) ascertain views on the relevance and importance of the trial; (2) determine the important parent/patient outcome measures; and (3) ascertain views on informed consent in a cluster randomized controlled trial. We conducted audio-recorded face-to-face, telephone and focus group interviews with parents and young people. Data were content analysed to generate information to address our specific consultation objectives. The setting was the north-western region of England. A total of 16 participants were interviewed: 2 parents of paediatric intensive care unit (PICU) survivors; 1 PICU survivor; and 13 young people from the former Medicines for Children Research Network. The trial objectives were deemed important and relevant, and participants considered the most important outcome measure to be the length of time on ventilation. Parents and young people did not consider written informed consent to be a necessary requirement in the context of this trial, rather awareness of unit participation in the trial was important with the opportunity of opting out of data collection. This consultation provided useful, pragmatic insights to inform trial design. We encountered significant challenges in recruiting parents and young people for this consultation exercise, and novel recruitment methods need to be considered for future work in this field. Patient and public involvement is essential to ensure that future trials answer parent-relevant questions and have meaningful outcome measures, as well as involving parents and young people in the general development of health care services.

Potential of hydrogel-forming and dissolving microneedles for use in paediatric populations

Development of formulations and drug delivery strategies for paediatric use is challenging, partially due to the age ranges within this population, resulting in varying requirements to achieve optimised patient outcomes. Although the oral route of drug delivery remains the preferred option, there are problematic issues, such as difficulty swallowing and palatability of medicines specific to this population. The parenteral route is not well accepted by children due to needle-related fear and pain. Accordingly, a plethora of alternative routes of drug administration have been investigated. Microneedles (MN) breach the stratum corneum (SC), the outermost layer of skin, increasing the number of drug substances amenable to transdermal delivery. This strategy involves the use of micron-sized needles to painlessly, and without drawing blood, create transient aqueous conduits in the SC. In this study, polymeric dissolving MN and hydrogel-forming MN were fabricated incorporating two model drugs commonly used in paediatric patients (caffeine and lidocaine hydrochloride). The potential efficacy of these MN for paediatric dosing was investigated via in vitro and in vivo studies. Views pertaining to MN technology were sought amongst school children in Northern Ireland, members of the UK general public and UK-based paediatricians, to determine perceived benefits, acceptance, barriers and concerns for adoption of this technology. In this study, polymeric MN were shown to substantially enhance skin permeability of the model therapeutic molecules in vitro and in vivo. In particular, hydrogel-forming MN led to a 6.1-fold increase in caffeine delivery whilst lidocaine HCl delivery was increased by 3.3-fold using dissolving MN in vitro. Application of caffeine-loaded MN led to a caffeine plasma concentration of 23.87μg/mL in rats at 24h. This research also highlighted a strong consensus regarding MN technology amongst schoolchildren, paediatricians and the general public, regarding potential use of MN in the paediatric population. Overall, 93.6% of general public respondents and 85.9% of paediatricians regarded the use of MN as a positive approach.

“It’s very complicated”: a qualitative study of medicines management in intermediate care facilities in Northern Ireland

Background: Intermediate care (IC) describes a range of services targeted at older people, aimed at preventing unnecessary hospitalisation, promoting faster recovery from illness and maximising independence. Older people are at increased risk of medication-related adverse events, but little is known about the provision of medicines management services in IC facilities. This study aimed to describe the current provision of medicines management services in IC facilities in Northern Ireland (NI) and to explore healthcare workers' (HCWs) and patients' views of, and attitudes towards these services and the IC concept. 

Methods: Semi-structured interviews were conducted, recorded, transcribed verbatim and analysed using a constant comparative approach with HCWs and patients from IC facilities in NI. 

Results: Interviews were conducted with 25 HCWs and 18 patients from 12 IC facilities in NI. Three themes were identified: 'concept and reality', 'setting and supply' and 'responsibility and review'. A mismatch between the concept of IC and the reality was evident. The IC facility setting dictated prescribing responsibilities and the supply of medicines, presenting challenges for HCWs. A lack of a standardised approach to responsibility for the provision of medicines management services including clinical review was identified. Whilst pharmacists were not considered part of the multidisciplinary team, most HCWs recognised a need for their input. Medicines management was not a concern for the majority of IC patients. 

Conclusions: Medicines management services are not integral to IC and medicine-related challenges are frequently encountered. Integration of pharmacists into the multidisciplinary team could potentially improve medicines management in IC.

A qualitative study of community pharmacists’ awareness of and involvement with intermediate care facilities

Rationale, aims and objectives: Intermediate care (IC) describes a range of services targeted at older people, aimed at preventing unnecessary hospitalisation, promoting faster recovery and maximising independence. The introduction of IC has created a new interface between primary and secondary care. Older people are known to be at an increased risk of medication-related problems when transferring between healthcare settings and pharmacists are often not included as part of IC multidisciplinary teams. This study aimed to explore community pharmacists’ (CPs) awareness of IC services and to investigate their views of and attitudes towards the medicines management aspects of such services, including the transfer of medication information.

Method: Semi-structured interviews were conducted, recorded, transcribed verbatim and analysed using a constant comparative approach with CPs practising in the vicinity of IC facilities in Northern Ireland, UK.

Results: Interviews were conducted with 16 CPs. Three themes were identified and named ‘left out of the loop’, ‘chasing things up’ and ‘closing the loop’. CPs felt that they were often ‘left out of the loop’ with regards to both their involvement with local IC services and communication across the healthcare interfaces. As a result, CPs resorted to ‘chasing things up’ as they had to proactively try to obtain information relating to patients’ medications. CPs viewed themselves as ideally placed to facilitate medicines management across the healthcare interfaces (i.e., ‘closing the loop’), but several barriers to potential services were identified.

Conclusion: CPs have limited involvement with IC services. There is a need for improvement of effective communication of patients’ medication information between secondary care, IC and community pharmacy. Increasing CP involvement may contribute to improving continuity of care across such healthcare interfaces, thereby increasing the person-centeredness of service provision.

Potentially harmful excipients in neonatal medicines: A pan-European observational study

Objectives We aimed to describe administration of eight potentially harmful excipients of interest (EOI)-parabens, polysorbate 80, propylene glycol, benzoates, saccharin sodium, sorbitol, ethanol and benzalkonium chloride-to hospitalised neonates in Europe and to identify risk factors for exposure. Methods All medicines administered to neonates during 1 day with individual prescription and demographic data were registered in a web-based point prevalence study. Excipients were identified from the Summaries of Product Characteristics. Determinants of EOI administration (geographical region, gestational age (GA), active pharmaceutical ingredient, unit level and hospital teaching status) were identified using multivariable logistical regression analysis. Results Overall 89 neonatal units from 21 countries participated. Altogether 2095 prescriptions for 530 products administered to 726 neonates were recorded. EOI were found in 638 (31%) prescriptions and were administered to 456 (63%) neonates through a relatively small number of products (n=142; 27%). Parabens, found in 71 (13%) products administered to 313 (43%) neonates, were used most frequently. EOI administration varied by geographical region, GA and route of administration. Geographical region remained a significant determinant of the use of parabens, polysorbate 80, propylene glycol and saccharin sodium after adjustment for the potential covariates including anatomical therapeutic chemical class of the active ingredient. Conclusions European neonates receive a number of potentially harmful pharmaceutical excipients. Regional differences in EOI administration suggest that EOI-free products are available and provide the potential for substitution to avoid side effects of some excipients.

Regular medication reviews for children and young people with ADHD

The National Institute for Health and Care Excellence's (2008) guidelines for the diagnosis and management of attention deficit hyperactivity disorder (ADHD) recommend a full clinical and psychological assessment by an appropriately trained clinician; this should include a detailed developmental and psychiatric history. Stimulant medications, which are Schedule II controlled drugs, are the most commonly prescribed medicines in the UK and across the world for the management of ADHD. Children and young people with a diagnosis of ADHD receiving these stimulant medications are required to attend regular review appointments with a consultant child and adolescent psychiatrist or specialist nurse under shared care guidelines with general practices, and it has long been recognized that appropriately educated nurses can assist in the management of ADHD. Owing to the pharmacological action of the stimulant medication on neurotransmission, there is potential for misuse and dependence. A growing body of evidence suggests that adolescents with ADHD can become involved in drug diversion and that the topic should be explored during assessment. The level of misuse of prescribed stimulants is increasing, and adolescents and young people with ADHD may misuse to enhance cognitive function for academic purposes. The following scenario highlights some of the challenges and opportunities for independent nurse prescribers working in child and adolescent mental health services.