Adherence to treatment in children and adolescents with cystic fibrosis: a cross-sectional, multi-method study investigating the influence of beliefs about treatment and parental depressive symptoms

BACKGROUND: Adherence to treatment is often reported to be low in children with cystic fibrosis. Adherence in cystic fibrosis is an important research area and more research is needed to better understand family barriers to adherence in order for clinicians to provide appropriate intervention. The aim of this study was to evaluate adherence to enzyme supplements, vitamins and chest physiotherapy in children with cystic fibrosis and to determine if any modifiable risk factors are associated with adherence.

METHODS: A sample of 100 children (≤18 years) with cystic fibrosis (44 male; median [range] 10.1 [0.2-18.6] years) and their parents were recruited to the study from the Northern Ireland Paediatric Cystic Fibrosis Centre. Adherence to enzyme supplements, vitamins and chest physiotherapy was assessed using a multi-method approach including; Medication Adherence Report Scale, pharmacy prescription refill data and general practitioner prescription issue data. Beliefs about treatments were assessed using refined versions of the Beliefs about Medicines Questionnaire-specific. Parental depressive symptoms were assessed using the Center for Epidemiologic Studies Depression Scale.

RESULTS: Using the multi-method approach 72% of children were classified as low-adherers to enzyme supplements, 59% low-adherers to vitamins and 49% low-adherers to chest physiotherapy. Variations in adherence were observed between measurement methods, treatments and respondents. Parental necessity beliefs and child age were significant independent predictors of child adherence to enzyme supplements and chest physiotherapy, but parental depressive symptoms were not found to be predictive of adherence.

CONCLUSIONS: Child age and parental beliefs about treatments should be taken into account by clinicians when addressing adherence at routine clinic appointments. Low adherence is more likely to occur in older children, whereas, better adherence to cystic fibrosis therapies is more likely in children whose parents strongly believe the treatments are necessary. The necessity of treatments should be reinforced regularly to both parents and children.

Does conurbation affect the risk of poor mental health? A population based record linkage study

To determine if urban residence is associated with an increased risk of anxiety/depression independent of psychosocial stressors, concentrated disadvantage or selective migration between urban and rural areas, this population wide record-linkage study utilised data on receipt of prescription medication linked to area level indicators of conurbation and disadvantage. An urban/rural gradient in anxiolytic and antidepressant use was evident that was independent of variation in population composition. This gradient was most pronounced amongst disadvantaged areas. Migration into increasingly urban areas increased the likelihood of medication. These results suggest increasing conurbation is deleterious to mental health, especially amongst residents of deprived areas

Bereavement After Informal Caregiving: Assessing Mental Health Burden Using Linked Population Data

Methods. We linked prescription records for antidepressant and anxiolytic drugs to characteristics and life-event data of members of the Northern Ireland Longitudinal Study (n = 317 264). Using a case-control design, we fitted logistic regression models, stratified by age, to model relative likelihood of mental health problems, using the proxy measures of mental health–related prescription.

Results. Both caregivers and bereaved individuals were estimated to be at between 20% and 50% greater risk for mental health problems than noncaregivers in similar circumstances (for bereaved working-age caregivers, odds ratio = 1.41; 95% confidence interval = 1.27, 1.56). For older people, there was no evidence of additional risk to bereaved caregivers, though there was for working-age people. Older people appeared to recover more quickly from caregiver bereavement.

High variability in the dosing of commonly used antibiotics revealed by a Europe-wide point prevalence study: implications for research and dissemination

BACKGROUND: Antibiotic dosing in neonates varies between countries and centres, suggesting suboptimal exposures for some neonates. We aimed to describe variations and factors influencing the variability in the dosing of frequently used antibiotics in European NICUs to help define strategies for improvement.

METHODS: A sub-analysis of the European Study of Neonatal Exposure to Excipients point prevalence study was undertaken. Demographic data of neonates receiving any antibiotic on the study day within one of three two-week periods from January to June 2012, the dose, dosing interval and route of administration of each prescription were recorded. The British National Formulary for Children (BNFC) and Neofax were used as reference sources. Risk factors for deviations exceeding ±25% of the relevant BNFC dosage recommendation were identified by multivariate logistic regression analysis.

RESULTS: In 89 NICUs from 21 countries, 586 antibiotic prescriptions for 342 infants were reported. The twelve most frequently used antibiotics - gentamicin, penicillin G, ampicillin, vancomycin, amikacin, cefotaxime, ceftazidime, meropenem, amoxicillin, metronidazole, teicoplanin and flucloxacillin - covered 92% of systemic prescriptions. Glycopeptide class, GA <32 weeks, 5(th) minute Apgar score <5 and geographical region were associated with deviation from the BNFC dosage recommendation. While the doses of penicillins exceeded recommendations, antibiotics with safety concerns followed (gentamicin) or were dosed below (vancomycin) recommendations.

CONCLUSIONS: The current lack of compliance with existing dosing recommendations for neonates needs to be overcome through the conduct of well-designed clinical trials with a limited number of antibiotics to define pharmacokinetics/pharmacodynamics, efficacy and safety in this population and by efficient dissemination of the results.

Post-diagnostic oral bisphosphonate use and colorectal cancer mortality: a population-based cohort study within the UK Clinical Practice Research Datalink

Background:We conducted the first study to investigate post-diagnostic oral bisphosphonates use and colorectal cancer-specific mortality.

Methods:Colorectal cancer patients were identified from the National Cancer Data Repository (1998–2007) and linked to the UK Clinical Practice Research Datalink, providing prescription records, and Office of National Statistics mortality data. Time-dependent Cox regression models investigated colorectal cancer-specific mortality in post-diagnostic bisphosphonate users.

Results:Overall, in 4791 colorectal cancer patients, there was no evidence of an association between bisphosphonate use and colorectal cancer-specific mortality (adjusted hazard ratio=1.11; 95% confidence interval 0.80, 1.54) or with drug frequency or type.

Conclusions:In this novel population-based cohort study, post-diagnostic bisphosphonate use was not associated with longer rates of colorectal cancer survival.

Digoxin use after diagnosis of breast cancer and survival: a population-based cohort study

Digoxin has been shown to have an estrogenic effect and is associated with increased risk of gynecomastia and estrogen-sensitive cancers such as breast and uterus cancer. These findings, particularly recent observations of increased breast cancer risk, raise questions about the safety of digoxin use in breast cancer patients. Therefore, we investigated whether digoxin use after breast cancer diagnosis increased the risk of breast cancer-specific mortality in breast cancer patients. A cohort of 17,842 breast cancer patients newly diagnosed from 1998 to 2009 was identified from English cancer registries (from the National Cancer Data Repository). This cohort was linked to the UK Clinical Practice Research Datalink (to provide digoxin and other prescription records) and to the Office of National Statistics mortality data (to identify breast cancer-specific deaths). Using time-dependent Cox regression models, unadjusted and adjusted hazard ratios (HR) and 95 % confidence intervals (CIs) were calculated for the association between post-diagnostic exposure to digoxin and breast cancer-specific and all-cause mortality. In 17,842 breast cancer patients, there were 2219 breast cancer-specific deaths. Digoxin users appeared to have increased breast cancer-specific mortality compared with non-users (HR 1.73; 95 % CI 1.39–2.15) but this association was entirely attenuated after adjustment for potential confounders (adjusted HR 0.91; 95 % CI 0.72–1.14). In this large population-based breast cancer cohort study, there was little evidence of an increase in breast cancer-specific mortality with digoxin use after diagnosis. These results provide some reassurance that digoxin use is safe in breast cancer patients.

Cost Effectiveness of Tooth Replacement Strategies for Partially Dentate Elders

Objectives: This study aimed to compare the cost effectiveness of conventional treatment using partial dentures with functionally-orientated treatment based on the shortened dental arch concept to replace missing teeth for partially dentate elders.
Methods: 44 partially dentate patients aged 65 years and older were recruited following routine dental assessment at a university dental hospital. Patients consented to and were randomly assigned to the two treatment arms. The conventional treatment group received a removable partial denture to replace all missing natural teeth. The functionally-orientated group were restored to a shortened dental arch of 10 occluding contacts using resin bonded bridgework. The costs associated with each treatment were recorded including laboratory charges, treatment time and opportunity costs. The impact on quality of life (OHRQoL) was measured using the 14-item Oral Health Impact Profile.
Results: Both groups reported improvements in OHRQoL after completion of treatment. For the conventional group, the mean OHIP-14 score decreased from 12.4 pre-operatively to 3.3 post-operatively (p<0.001). In the functionally-orientated group the OHIP-14 score decreased from 11.4 to 1.8 following treatment (p<0.001). On average the conventional treatment group required 8.3 clinic visits as compared to 4.4 visits for the functionally-orientated group. The mean total treatment time was 183 minutes 19 seconds for the conventional group versus 124 minutes 8 seconds for the functionally-orientated group. The conventional treatment group had an average of 6.33 teeth replaced at a laboratory cost of 337.31 Euros. The functionally-orientated group had an average of 2.64 teeth replaced at a laboratory cost of 244.05 Euros.
Conclusions: Restoration to a shortened dental arch using functionally-orientated treatment resulted in a similar improvement in OHRQoL with fewer clinic visits, less operative time and at a lower laboratory cost compared with conventional treatment.

Quasi-periodic stacks of semiconductor layers: Combinatorial frequency generation

The nonlinear scattering and combinatorial frequency generation by the quasi-periodic Fibonacci and Thue-Morse stacks of semiconductor layers have been investigated taking into account the nonlinear charge dynamics. It has been shown that the mixing processes in passive semiconductor structures are driven by the competitive effects of the collision of charges and resonance interactions of carriers with pump waves. The effects of the stack arrangements and constituent layer parameters on the efficiency of the combinatorial frequency generation are discussed. 

Statin use after colorectal cancer diagnosis and survival: a population-based cohort study

PURPOSE: To investigate whether statins used after colorectal cancer diagnosis reduce the risk of colorectal cancer-specific mortality in a cohort of patients with colorectal cancer.

PATIENTS AND METHODS: A cohort of 7,657 patients with newly diagnosed stage I to III colorectal cancer were identified from 1998 to 2009 from the National Cancer Data Repository (comprising English cancer registry data). This cohort was linked to the United Kingdom Clinical Practice Research Datalink, which provided prescription records, and to mortality data from the Office of National Statistics (up to 2012) to identify 1,647 colorectal cancer-specific deaths. Time-dependent Cox regression models were used to calculate hazard ratios (HR) for cancer-specific mortality and 95% CIs by postdiagnostic statin use and to adjust these HRs for potential confounders.

RESULTS: Overall, statin use after a diagnosis of colorectal cancer was associated with reduced colorectal cancer-specific mortality (fully adjusted HR, 0.71; 95% CI, 0.61 to 0.84). A dose-response association was apparent; for example, a more marked reduction was apparent in colorectal cancer patients using statins for more than 1 year (adjusted HR, 0.64; 95% CI, 0.53 to 0.79). A reduction in all-cause mortality was also apparent in statin users after colorectal cancer diagnosis (fully adjusted HR, 0.75; 95% CI, 0.66 to 0.84).

CONCLUSION: In this large population-based cohort, statin use after diagnosis of colorectal cancer was associated with longer rates of survival.

Predictive Factors for Local Control in Primary and Metastatic Lung Tumours after Four to Five Fraction Stereotactic Ablative Body Radiotherapy: A Single Institution's Comprehensive Experience

AIMS: We report the outcomes of a large lung stereotactic ablative body radiotherapy (SABR) programme for primary non-small cell lung cancer (NSCLC) and pulmonary metastases. The primary study aim was to identify factors predictive for local control.

MATERIALS AND METHODS: In total, 311 pulmonary tumours in 254 patients were treated between 2008 and 2011 with SABR using 48-60 Gy in four to five fractions. Local, regional and distant failure data were collected prospectively, whereas other end points were collected retrospectively. Potential clinical and dosimetric predictors of local control were evaluated using univariate and multivariate analyses.

RESULTS: Of the 311 tumours, 240 were NSCLC and 71 were other histologies. The 2 year local control rate was 96% in stage I NSCLC, 76% in colorectal cancer (CRC) metastases and 91% in non-lung/non-CRC metastases. Predictors of better local control on multivariate analysis were non-CRC tumours and a larger proportion of the planning target volume (PTV) receiving ≥100% of the prescribed dose (higher PTV V100). Among the 45 CRC metastases, a higher PTV V100 and previous chemotherapy predicted for better local control.

CONCLUSIONS: Lung SABR of 48-60 Gy/four to five fractions resulted in high local control rates for all tumours except CRC metastases. Covering more of the PTV with the prescription dose (a higher PTV V100) also resulted in superior local control.

Sporting Justice: An Arbitrator's Perspective

Drawing on my experience of a number of sports dispute resolution tribunals in the UK and Ireland (such as Sports Resolutions UK; Just Sport Ireland; the Football Association of Ireland’s Disciplinary Panel and the Gaelic Athletic Association’s Dispute Resolution Authority) I intend to use this paper to review the legal arguments typically made in sports-related arbitrations. These points of interest can be summarised as a series of three questions: the fairness question; the liability question; the penalty question.

In answer to the fairness question, the aim is to give a brief outline on best practice in establishing a "fair" sports disciplinary tribunal. The answer, I believe, is always twofold in nature: first, and to paraphrase Lord Steyn in R v Secretary of State For The Home Department, Ex Parte Daly [2001] UKHL 26 at [28] "in law, context is everything" – translated into the present matter, this means that in sports disciplinary cases, the more serious the charges against the individual (in terms of reputational damage, economic impact and/or length of sanction); the more tightly wrapped the procedural safeguards surrounding any subsequent disciplinary hearing must be. A fair disciplinary system will be discussed in the context of the principles laid down in Article 8 of the World Anti-Doping Code which, in effect, acts as sport’s Article 6 of the ECHR on a right to a fair trial.

Following on from the above, in the 60 or so sports arbitrations that I have heard, there are two further points of interest. First, the claim before the arbitral panel will often be framed in an argument that, for various reasons of substantive and procedural irregularity, the sanction imposed on the appellant should be quashed ("the liability"). Second, and in alternative, that the sanction imposed was wholly disproportionate ("the penalty").

The liability issue usually breaks down into two further questions. First, what is the nature of the legal duty upon a sports body in exercising its disciplinary remit? Second, to what extent does a de novo hearing on appeal cure any apparent defects in a hearing of first instance? The first issue often results in an arbitral panel debating the contra preferentum approach to the interpretation of a contested rule i.e., the sports body’s rules in question are so ambiguous that they should be interpreted in a manner to the detriment of the rule maker and in favour of the appellant. On the second matter, it now appears to be a general principle of sports law, administrative law and even human rights law that even if a violation of the principles of natural justice takes place at the first instance stage of a disciplinary process, they may be cured on de novo appeal. Authority for this approach can be found at the Court of Arbitration for Sport and in particular in CAS 2009/A/1920 FK Pobeda, Aleksandar Zabrcanec, Nikolce Zdraveski v UEFA at para 87.

The question on proportionality asks what, aside from precedent found within the decisions of the sports body in question, are the general legal principles against which a sanction by a sports disciplinary body can be benchmarked in order to ascertain whether it is disproportionate in length or even irrational in nature?

On the matter of (dis)proportionality of sanction, the debate is usually guided by the authority in Bradley v the Jockey Club [2004] EWHC 2164 (QB) and affirmed at [2005] EWCA Civ 1056. The Bradley principles on proportionality of sports-specific sanctions, recently cited with approval at the Court of Arbitration for Sport, will be examined in this presentation.

Finally, an interesting application of many of the above principles (and others such as the appropriate standard of proof in sports disciplinary procedures) can be made to recent match-fixing or corruption related hearings held by the British Horse Racing Authority, the integrity units of snooker and tennis, and at the Court of Arbitration for Sport.

The Impact of Colleague Peer Review on the Radiotherapy Treatment Planning Process in the Radical Treatment of Lung Cancer

AIMS: Modern radiotherapy uses techniques to reliably identify tumour and reduce target volume margins. However, this can potentially lead to an increased risk of geographic miss. One source of error is the accuracy of target volume delineation (TVD). Colleague peer review (CPR) of all curative-intent lung cancer plans has been mandatory in our institution since May 2013. At least two clinical oncologists review plans, checking treatment paradigm, TVD, prescription dose tumour and critical organ tolerances. We report the impact of CPR in our institution.

MATERIALS AND METHODS: Radiotherapy treatment plans of all patients receiving radical radiotherapy were presented at weekly CPR meetings after their target volumes were reviewed and signed off by the treating consultant. All cases and any resultant change to TVD (including organs at risk) or treatment intent were recorded in our prospective CPR database. The impact of CPR over a 13 month period from May 2013 to June 2014 is reported.

RESULTS: One hundred and twenty-two patients (63% non-small cell lung carcinoma, 17% small cell lung carcinoma and 20% 'clinical diagnosis') were analysed. On average, 3.2 cases were discussed per meeting (range 1-8). CPR resulted in a change in treatment paradigm in 3% (one patient proceeded to induction chemotherapy, two patients had high-dose palliative radiotherapy). Twenty-one (17%) had a change in TVD and one (1%) patient had a change in dose prescription. In total, 6% of patients had plan adjustment after review of dose volume histogram.

CONCLUSION: The introduction of CPR in our centre has resulted in a change in a component of the treatment plan for 27% of patients receiving curative-intent lung radiotherapy. We recommend CPR as a mandatory quality assurance step in the planning process of all radical lung plans.

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.

Inappropriate prescribing of combination inhalers in Northern Ireland: retrospective cross-sectional cohort study of prescribing practice in primary care

BACKGROUND: Asthma management guidelines advocate a stepwise approach to asthma therapy, including the addition of a long-acting bronchodilator to inhaled steroid therapy at step 3. This is almost exclusively prescribed as inhaled combination therapy.

AIMS: To examine whether asthma prescribing practice for inhaled combination therapy (inhaled corticosteroid/long-acting β2-agonist (ICS/LABA)) in primary care in Northern Ireland is in line with national asthma management guidelines.

METHODS: Using data from the Northern Ireland Enhanced Prescribing Database, we examined initiation of ICS/LABA in subjects aged 5-35 years in 2010.

RESULTS: A total of 2,640 subjects (67%) had no inhaled corticosteroid monotherapy (ICS) in the study year or six months of the preceding year (lead-in period) and, extending this to a 12-month lead-in period, 52% had no prior ICS. 41% of first prescriptions for ICS/LABA were dispensed in January to March. Prior to ICS/LABA prescription, in the previous six months only 17% had a short-acting β2-agonist (SABA) dispensed, 5% received oral steroids, and 17% received an antibiotic.

CONCLUSIONS: ICS/LABA therapy was initiated in the majority of young subjects with asthma without prior inhaled steroid therapy. Most prescriptions were initiated in the January to March period. However, the prescribing of ICS/LABA did not appear to be driven by asthma symptoms (17% received SABA in the previous 6 months) or severe asthma exacerbation (only 5% received oral steroids). Significant reductions in ICS/LABA, with associated cost savings, would occur if the asthma prescribing guidelines were followed in primary care.

Dimensions of Suicide Research: Substance misuse in life and death in a 2-year cohort of suicides

Background
While substance misuse is a key risk factor in suicide relatively little is known about the relationship between lifetime misuse and misuse in suicide.

Aim
To examine the relationship between a history of substance misuse and misuse at the time of a suicide.

Method
Linkage of Coroner reports of 403 suicides occurring over two years with associated primary care records. History of substance misuse was defined as alcohol misuse and/or prescription or illicit drug misuse, for which medical help was sought.

Results
With alcohol misuse: 65% of the cohort had previously sought help and 42% were intoxicated at the suicide (with 30% of these seeing their GP in the previous year). With misuse of other substances: 54% of the cohort were tested for blood toxicology (37% of these tested positive) - with positive toxicology defined as an excess of prescription drugs over the therapeutic minima and/or detection of illicit substances. Those tested were more likely to be young and have a history of drug abuse.

Conclusion
Understanding the links between substance misuse and the use of substances in conjunction with the act of suicide is discussed in light of the study results and current pathology and coroner practices.