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1.  Understanding “revolving door” patients in general practice: a qualitative study 
BMC Family Practice  2014;15:33.
‘Revolving door’ patients in general practice are repeatedly removed from general practitioners’ (GP) lists. This paper reports a qualitative portion of the first mixed methods study of these marginalised patients.
We conducted qualitative semi-structured interviews with six practitioner services staff and six GPs in Scotland, utilizing Charmazian grounded theory to characterise ‘revolving door’ patients and their impact from professionals’ perspectives.
‘Revolving door’ patients were reported as having three necessary characteristics; they had unreasonable expectations, exhibited inappropriate behaviours and had unmet health needs. A range of boundary breaches were reported too when ‘revolving door’ patients interacted with NHS staff.
We utilise the ‘sensitising concepts’ of legitimacy by drawing on literature about ‘good and bad’ patients and ‘dirty work designations.’ We relate these to the core work of general practice and explore the role that medical and moral schemas have in how health service professionals understand and work with ‘revolving door’ patients. We suggest this may have wider relevance for the problem doctor patient relationship literature.
PMCID: PMC3930014  PMID: 24524363
2.  Reducing drug related deaths: a pre-implementation assessment of knowledge,barriers and enablers for naloxone distribution through general practice 
BMC Family Practice  2014;15:12.
The Scottish Naloxone Programme aims to reduce Scotland’s high number of drug-related deaths (DRDs) caused by opiate overdose. It is currently implemented through specialist drug services but General Practitioners (GPs) are likely to have contact with drug using patients and their families and are therefore in an ideal position to direct them to naloxone schemes, or provide it themselves. This research gathered baseline data on GP’s knowledge of and willingness to be involved in DRD prevention, including naloxone administration, prior to the implementation of primary care based delivery.
Mixed methods were used comprising a quantitative, postal survey and qualitative telephone interviews. A questionnaire was sent to 500 GPs across Scotland. An initial mailing was followed by a reminder. A shortened questionnaire containing seven key questions was posted as a final reminder. Telephone interviews were conducted with 17 GPs covering a range of demographic characteristics and drug user experience.
A response rate of 55% (240/439) was achieved. There was some awareness of the naloxone programme but little involvement (3.3%), 9% currently provided routine overdose prevention, there was little involvement in displaying overdose prevention information (<20%). Knowledge of DRD risk was mixed. There was tentative willingness to be involved in naloxone prescribing with half of respondents willing to provide this to drug users or friends/family. However half were uncertain GP based naloxone provision was essential to reduce DRDs.
Factors enabling naloxone distribution were: evidence of effectiveness, appropriate training, and adding to the local formulary. Interviewees had limited awareness of what naloxone distribution in primary care may involve and considered naloxone supply as a specialist service rather than a core GP role. Wider attitudinal barriers to involvement with this group were expressed.
There was poor awareness of the Scottish National Naloxone Programme in participants. Results indicated GPs did not currently feel sufficiently skilled or knowledgeable to be involved in naloxone provision. Appropriate training was identified as a key requirement.
PMCID: PMC3898062  PMID: 24428947
3.  Language and social/emotional problems identified at a universal developmental assessment at 30 months 
BMC Pediatrics  2013;13:206.
Preschool language and neurodevelopmental problems often persist and impede learning. The aims of the current study are to assess the uptake of a new universal 30 month health visitor contact and to quantify the prevalence of language delay and social/emotional difficulties.
All families of 30 month old children in four Glasgow localities were offered a visit from their health visitor. Structured data were collected relating to language, social and emotional development using three instruments; The Strengths and Difficulties Questionnaire (SDQ), the abbreviated Sure Start Language Measure and a two-item language screen.
From an eligible population of 543 children, there was a 90% return rate of contact forms from the health visitors, and assessments were completed on 78% of eligible children. Visit completion rates did not differ significantly by socio-economic status. 3-8% of children were reported to have language delay depending on the method of assessment. 8.8% of children scored in the “abnormal” range of SDQ total difficulties scores and 31.1% had an abnormality in at least one subscale. There was substantial overlap between language delay and abnormal scores on the SDQ.
Universal assessment of neurodevelopmental function at 30 months identified a significant proportion of children, including those previously considered at low risk, with both language and social/emotional difficulties. Further work is required to assess the precise nature of these difficulties and to assess the potential impact on services.
PMCID: PMC3878792  PMID: 24330767
Child development; Language delay; Socio-emotional development; Screening; Preschool assessment; Child health surveillance; Child psychiatry
4.  Prediction of 7-year psychopathology from mother-infant joint attention behaviours: a nested case–control study 
BMC Pediatrics  2013;13:147.
To investigate whether later diagnosis of psychiatric disorder can be predicted from analysis of mother-infant joint attention (JA) behaviours in social-communicative interaction at 12 months.
Using data from a large contemporary birth cohort, we examined 159 videos of a mother-infant interaction for joint attention behaviour when children were aged one year, sampled from within the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort. Fifty-three of the videos involved infants who were later considered to have a psychiatric disorder at seven years and 106 were same aged controls. Psychopathologies included in the case group were disruptive behaviour disorders, oppositional-conduct disorder, attention-deficit/hyperactivity disorder, pervasive development disorder, anxiety and depressive disorders. Psychiatric diagnoses were obtained using the Development and Wellbeing Assessment when the children were seven years old.
None of the three JA behaviours (shared look rate, shared attention rate and shared attention intensity) showed a significant association with the primary outcome of case–control status. Only shared look rate predicted any of the exploratory sub-diagnosis outcomes and was found to be positively associated with later oppositional-conduct disorders (OR [95% CI]: 1.5 [1.0, 2.3]; p = 0.041).
JA behaviours did not, in general, predict later psychopathology. However, shared look was positively associated with later oppositional-conduct disorders. This suggests that some features of JA may be early markers of later psychopathology. Further investigation will be required to determine whether any JA behaviours can be used to screen for families in need of intervention.
PMCID: PMC3848970  PMID: 24063312
Avon longitudinal study of parents and children (ALSPAC), Autism, Attention deficit hyperactivity disorder (ADHD), Disruptive behaviour disorders, Joint attention behaviours
5.  Correction: Guided Self-Help Cognitive Behavioural Therapy for Depression in Primary Care: A Randomised Controlled Trial 
PLoS ONE  2013;8(9):10.1371/annotation/998d1a71-7c06-4ebd-8deb-d5db5ad21c31.
PMCID: PMC3813318  PMID: 24205406
6.  Maximizing Survival Benefit With Primary Prevention ICD Therapy in a Heart Failure Population 
Circulation  2009;120(10):835-842.
Although implantable cardioverter defibrillator (ICD) therapy reduces mortality in moderately symptomatic heart failure patients with an ejection fraction ≤35%, many such patients do not require ICD shocks over long-term follow-up.
Using a modification of a previously validated risk prediction model based on routine clinical variables, we examined the relationship between baseline predicted mortality risk and the relative and absolute survival benefits of ICD treatment in the primary prevention Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT).
In the placebo arm, predicted 4-year mortality grouped into 5 equal-sized risk groups varied from 12% to 50% (c statistic=0.71), while the proportion of SCD in those same risk groups decreased from 52% to 24% of all deaths. ICD treatment decreased relative risk of SCD by 88% in the lowest risk group vs. 24% in the highest risk group (p =0.009 for the interaction), and relative risk of total mortality by 54% in the lowest risk group vs. no benefit (2%) in the highest risk group (p =0.014 for the interaction). Absolute 4-year mortality reductions were 6.6%, 8.8%, 10.6%, 14.0% and −4.9% across risk quintiles. In highest risk patients (predicted annual mortality >20%), no benefit of ICD treatment was seen. Projected over each patient’s predicted life span, ICD treatment added 6.3, 4.1, 3.0, 1.9, and 0.2 additional years of life in the lowest to highest risk groups, respectively.
A clinical risk-prediction model identified subsets of moderately symptomatic heart failure patients in SCD-HeFT in whom single lead ICD therapy was of no benefit and other subsets in which benefit was substantial.
PMCID: PMC3774781  PMID: 19704100
Arrhythmias; clinical electrophysiology; drugs; Congestive Heart Failure; Ablation/ICD/surgery; Health policy and outcome research
7.  Central and peripheral quadriceps fatigue in congestive heart failure☆ 
International Journal of Cardiology  2013;167(6):2594-2599.
The clinical syndrome of heart failure includes exercise limitation that is not directly linked to measures of cardiac function. Quadriceps fatigability may be an important component of this and this may arise from peripheral or central factors.
Methods and results
We studied 10 men with CHF and 10 healthy age-matched controls. Compared with a rest condition, 10 min after incremental maximal cycle exercise, twitch quadriceps force in response to supramaximal magnetic femoral nerve stimulation fell in both groups (CHF 14.1% ± 18.1%, p = 0.037; Control: 20.8 ± 11.0%, p < 0.001; no significant difference between groups). There was no significant change in quadriceps maximum voluntary contraction voluntary force. The difference in the motor evoked potential (MEP) response to transcranial magnetic stimulation of the motor cortex between rest and exercise conditions at 10 min, normalised to the peripheral action potential, also fell significantly in both groups (CHF: 27.3 ± 38.7%, p = 0.037; Control: 41.1 ± 47.7%, p = 0.024). However, the fall in MEP was sustained for a longer period in controls than in patients (p = 0.048).
The quadriceps is more susceptible to fatigue, with a similar fall in TwQ occurring in CHF patients at lower levels of exercise. This is associated with no change in voluntary activation but a lesser degree of depression of quadriceps motor evoked potential.
PMCID: PMC3776927  PMID: 22795722
Brain; Exercise; Muscles; Transcranial magnetic stimulation
8.  A Feasibility Randomised Controlled Trial of the New Orleans Intervention for Infant Mental Health: A Study Protocol 
The Scientific World Journal  2013;2013:838042.
Child maltreatment is associated with life-long social, physical, and mental health problems. Intervening early to provide maltreated children with safe, nurturing care can improve outcomes. The need for prompt decisions about permanent placement (i.e., regarding adoption or return home) is internationally recognised. However, a recent Glasgow audit showed that many maltreated children “revolve” between birth families and foster carers. This paper describes the protocol of the first exploratory randomised controlled trial of a mental health intervention aimed at improving placement permanency decisions for maltreated children. This trial compares an infant's mental health intervention with the new enhanced service as usual for maltreated children entering care in Glasgow. As both are new services, the trial is being conducted from a position of equipoise. The outcome assessment covers various fields of a child's neurodevelopment to identify problems in any ESSENCE domain. The feasibility, reliability, and developmental appropriateness of all outcome measures are examined. Additionally, the potential for linkage with routinely collected data on health and social care and, in the future, education is explored. The results will inform a definitive randomised controlled trial that could potentially lead to long lasting benefits for the Scottish population and which may be applicable to other areas of the world. This trial is registered with (NC01485510).
PMCID: PMC3655679  PMID: 24023537
9.  Language Delay Is Not Predictable from Available Risk Factors 
The Scientific World Journal  2013;2013:947018.
Aims. To investigate factors associated with language delay in a cohort of 30-month-old children and determine if identification of language delay requires active contact with families. Methods. Data were collected at a pilot universal 30-month health contact. Health visitors used a simple two-item language screen. Data were obtained for 315 children; language delay was found in 33. The predictive capacity of 13 variables which could realistically be known before the 30-month contact was analysed. Results. Seven variables were significantly associated with language delay in univariate analysis, but in logistic regression only five of these variables remained significant. Conclusion. The presence of one or more risk factors had a sensitivity of 89% and specificity of 45%, but a positive predictive value of only 15%. The presence of one or more of these risk factors thus can not reliably be used to identify language delayed children, nor is it possible to define an “at risk” population because male gender was the only significant demographic factor and it had an unacceptably low specificity (52.5%). It is not possible to predict which children will have language delay at 30 months. Identification of this important ESSENCE disorder requires direct clinical contact with all families.
PMCID: PMC3618945  PMID: 23576912
10.  The bacterial parasite Pasteuria ramosa is not killed if it fails to infect: implications for coevolution 
Ecology and Evolution  2012;3(2):197-203.
Strong selection on parasites, as well as on hosts, is crucial for fueling coevolutionary dynamics. Selection will be especially strong if parasites that encounter resistant hosts are destroyed and diluted from the local environment. We tested whether spores of the bacterial parasite Pasteuria ramosa were passed through the gut (the route of infection) of their host, Daphnia magna, and whether passaged spores remained viable for a “second chance” at infecting a new host. In particular, we tested if this viability (estimated via infectivity) depended on host genotype, whether or not the genotype was susceptible, and on initial parasite dose. Our results show that Pasteuria spores generally remain viable after passage through both susceptible and resistant Daphnia. Furthermore, these spores remained infectious even after being frozen for several weeks. If parasites can get a second chance at infecting hosts in the wild, selection for infection success in the first instance will be reduced. This could also weaken reciprocal selection on hosts and slow the coevolutionary process.
PMCID: PMC3586630  PMID: 23467806
Daphnia; dilution effect; host–parasite coevolution; Pasteuria
11.  Guided Self-Help Cognitive Behavioural Therapy for Depression in Primary Care: A Randomised Controlled Trial 
PLoS ONE  2013;8(1):e52735.
Access to Cognitive behavioural therapy (CBT) for depression is limited. One solution is CBT self-help books.
Trial Objectives: To assess the impact of a guided self-help CBT book (GSH-CBT) on mood, compared to treatment as usual (TAU).
Hypotheses:GSH-CBT will have improved mood and knowledge of the causes and treatment of depression compared to the control receiving TAUGuided self-help will be acceptable to patients and staff.
Methods and Findings
Participants: Adults attending seven general practices in Glasgow, UK with a BDI-II score of ≥14. 141 randomised to GSH-CBT and 140 to TAU.
Interventions: RCT comparing ‘Overcoming Depression: A Five Areas Approach’ book plus 3–4 short face to face support appointments totalling up to 2 hours of guided support, compared with general practitioner TAU.
Primary outcome: The BDI (II) score at 4 months.
Numbers analysed: 281 at baseline, 203 at 4 months (primary outcome), 117 at 12 months.
Outcome: Mean BDI-II scores were lower in the GSH-CBT group at 4 months by 5.3 points (2.6 to 7.9, p<0.001). At 4 and 12 months there were also significantly higher proportions of participants achieving a 50% reduction in BDI-II in the GSH-CBT arm. The mean support was 2 sessions with 42.7 minutes for session 1, 41.4 minutes for session 2 and 40.2 minutes of support for session 3.
Adverse effects/Harms: Significantly less deterioration in mood in GSH-CBT (2.0% compared to 9.8% in the TAU group for BDI—II category change).
Weaknesses: Our follow-up rate of 72.2% at 4 months is better than predicted but is poorer at 12 months (41.6%). In the GSH-CBT arm, around 50% of people attended 2 or fewer sessions. 22% failed to take up treatment.
GSH-CBT is substantially more effective than TAU.
Trial Registration ISRCTN13475030
PMCID: PMC3543408  PMID: 23326352
12.  A Novel Medical Treatment of Cushing's Due to Ectopic ACTH in a Patient With Neurofibromatosis Type 1 
A 64-year-old male presented with neurofibromatosis 1 and Cushing’s syndrome. Clinically he was over weight, depressed with extensive skin bruising and hypertension. His 24 hours urinary metanephrines, urinary 5HIAA, gut peptides and chromgranin levels were normal. His renal function and renal MRI scan was also normal. His cortisol failed to suppress on overnight dexamethsone suppression test. His low dose dexamethasone suppression with CRH stimulation showed failure of suppression of cortisol to < 50 nmol/L and ACTH was measurable at 10 ng/L on day 3. There was no response of ACTH or cortisol to CRH stimulation. His ACTH precursors were high at 126 pmol/L consistent with defective pro-opiomelanocortin (POMC) processing suggesting an ectopic source of ACTH production. The MRI scan of his pituitary and CT scan of the adrenal glands was normal. His octreotide scan was negative. The source of his ectopic ACTH was most likely a large retroperitoneal plexiform neurofibroma seen on CT abdomen that had undergone malignant peripheral nerve sheath tumour transformation on histology. He was a poor surgical risk for tumour debulking procedure. In view of the available literature and role of c-kit signalling in neurofibromatosis, he was treated with Imitinib. Four months after the treatment his Cushings had resolved on biochemical testing. After a year his plexiform neurofibroma has not increased in size. To our knowledge, this is the first case of NF1 associated with clinical and biochemical features of Cushing’s secondary to ectopic ACTH due to MPNST in a plexiform neurofibroma and its resolution on treatment with imatinib.
PMCID: PMC3693655  PMID: 23853621
Adrenal Gland Diseases; Adrenocortical Hyperfunction
13.  How evidence-based is an 'evidence-based parenting program'? A PRISMA systematic review and meta-analysis of Triple P 
BMC Medicine  2012;10:130.
Interventions to promote positive parenting are often reported to offer good outcomes for children but they can consume substantial resources and they require rigorous appraisal.
Evaluations of the Triple P parenting program were subjected to systematic review and meta-analysis with analysis of biases. PsychInfo, Embase and Ovid Medline were used as data sources. We selected published articles reporting any child-based outcome in which any variant of Triple P was evaluated in relation to a comparison condition. Unpublished data, papers in languages other than English and some book chapters were not examined. Studies reporting Eyberg Child Behavior Inventory or Child Behavior Checklist scores as outcomes were used in the meta-analysis.
A total of 33 eligible studies was identified, most involving media-recruited families. Thirty-one of these 33 studies compared Triple P interventions with waiting list or no-treatment comparison groups. Most papers only reported maternal assessments of child behavior. Twenty-three papers were incorporated in the meta-analysis. No studies involved children younger than two-years old and comparisons of intervention and control groups beyond the duration of the intervention were only possible in five studies. For maternally-reported outcomes the summary effect size was 0.61 (95%CI 0.42, 0.79). Paternally-reported outcomes following Triple P intervention were smaller and did not differ significantly from the control condition (effect size 0.42 (95%CI -0.02, 0.87)). The two studies involving an active control group showed no between-group differences. There was limited evidence of publication bias, but there was substantial selective reporting bias, and preferential reporting of positive results in article abstracts. Thirty-two of the 33 eligible studies were authored by Triple-P affiliated personnel. No trials were registered and only two papers contained conflict of interest statements.
In volunteer populations over the short term, mothers generally report that Triple P group interventions are better than no intervention, but there is concern about these results given the high risk of bias, poor reporting and potential conflicts of interest. We found no convincing evidence that Triple P interventions work across the whole population or that any benefits are long-term. Given the substantial cost implications, commissioners should apply to parenting programs the standards used in assessing pharmaceutical interventions.
See related commentary:
PMCID: PMC3532197  PMID: 23121760
parenting; public health; child psychology; behavioral family intervention; systematic review; meta-analysis
14.  The disappearance of the “revolving door” patient in Scottish general practice: successful policies 
BMC Family Practice  2012;13:95.
We describe the health of "revolving door" patients in general practice in Scotland, estimate changes in their number over the timescale of the study, and explore reasons for changes, particularly related to NHS and government policy.
A mixed methods predominantly qualitative study, using a grounded theory approach, set in Scottish general practice. Semi-structured interviews were conducted with professional key informants, 6 Practitioner Services staff who administer the GP registration system and 6 GPs with managerial or clinical experience of working with “revolving door” patients. Descriptive statistical analysis and qualitative analysis of patient removal episodes linked with routine hospital admissions, outpatient appointments, drug misuse treatment episodes and deaths were carried out with cohorts of “revolving door” patients identified from 1999 to 2005 in Scotland.
A “revolving door” patient is removed 4 or more times from GP lists in 7 years. Patients had complex health issues including substance misuse, psychiatric and physical health problems and were at high risk of dying. There was a dramatic reduction in the number of “revolving door” patients during the course of the study.
“Revolving door” patients in general practice had significant health problems. Their numbers have reduced dramatically since 2004 and this probably resulted from improved drug treatment services, pressure from professional bodies to reduce patient removals and the positive ethical regulatory and financial climate of the 2004 GMS GP contract. This is a positive development for the NHS.
PMCID: PMC3528483  PMID: 23035887
15.  "A powerful intervention: general practitioners'; use of sickness certification in depression" 
BMC Family Practice  2012;13:82.
Depression is frequently cited as the reason for sickness absence, and it is estimated that sickness certificates are issued in one third of consultations for depression. Previous research has considered GP views of sickness certification but not specifically in relation to depression.
This study aimed to explore GPs views of sickness certification in relation to depression.
A purposive sample of GP practices across Scotland was selected to reflect variations in levels of incapacity claimants and antidepressant prescribing. Qualitative interviews were carried out between 2008 and 2009.
A total of 30 GPs were interviewed. A number of common themes emerged including the perceived importance of GP advocacy on behalf of their patients, the tensions between stakeholders involved in the sickness certification system, the need to respond flexibly to patients who present with depression and the therapeutic nature of time away from work as well as the benefits of work. GPs reported that most patients with depression returned to work after a short period of absence and that it was often difficult to predict which patients would struggle to return to work.
GPs reported that dealing with sickness certification and depression presents distinct challenges. Sickness certificates are often viewed as powerful interventions, the effectiveness of time away from work for those with depression should be subject to robust enquiry.
PMCID: PMC3441202  PMID: 22877237
Depression; Mood disorder; Primary care; Occupational; Environmental medicine; Doctor-patient relationship; Mental health
16.  Daphnia magna shows reduced infection upon secondary exposure to a pathogen 
Biology Letters  2012;8(6):972-975.
Previous pathogen exposure is an important predictor of the probability of becoming infected. This is deeply understood for vertebrate hosts, and increasingly so for invertebrate hosts. Here, we test if an initial pathogen exposure changes the infection outcome to a secondary pathogen exposure in the natural host–pathogen system Daphnia magna and Pasteuria ramosa. Hosts were initially exposed to an infective pathogen strain, a non-infective pathogen strain or a control. The same hosts underwent a second exposure, this time to an infective pathogen strain, either immediately after the initial encounter or 48 h later. We observed that an initial encounter with a pathogen always conferred protection against infection compared with controls.
PMCID: PMC3497123  PMID: 22875818
within-generation immune priming; Daphnia; immunological loitering
17.  General practitioner provision of preventive child health care: analysis of routine consultation data 
BMC Family Practice  2012;13:73.
GPs contribute to preventive child health care in various ways, including provision of child health surveillance (CHS) reviews, opportunistic preventive care, and more intensive support to vulnerable children. The number of CHS reviews offered in Scotland was reduced from 2005. This study aimed to quantify GPs’ provision of different types of preventive care to pre-school children before and after the changes to the CHS system.
GP consultation rates with children aged 0–4 years were examined for the 2½ years before and after the changes to the CHS system using routinely available data from 30 practices in Scotland. Consultations for CHS reviews; other aspects of preventive care; and all reasons were considered.
Prior to the changes to the CHS system, GPs often contributed to CHS reviews at 6–8 weeks and 8–9 and 39–42 months. Following the changes, GP provision of the 6–8 week review continued but other reviews essentially ceased. Few additional consultations with pre-school children are recorded as involving other aspects of preventive care, and the changes to CHS have had no impact on this. In the 2½ years before and after the changes, consultations recorded as involving any form of preventive care accounted for 11% and 7.5% respectively of all consultations with children aged 0–4 years, with the decline due to reductions in CHS reviews.
Effective preventive care through the early years can help children secure good health and developmental outcomes. GPs are well placed to contribute to the provision of such care. Consultations focused on preventive care form a small minority of GPs’ contacts with pre-school children, however, particularly since the reduction in the number of CHS reviews.
PMCID: PMC3460766  PMID: 22862924
Child health; General practice; Preventive health services; Health promotion; General practitioners; Health visitors
18.  SERCA2a Gene Transfer Decreases SR Calcium Leak and Reduces Ventricular Arrhythmias in a Model of Chronic Heart Failure 
Sarcoplasmic reticulum calcium ATPase 2a (SERCA2a) gene therapy improves mechanical function in heart failure, and is under evaluation in a clinical trial. A critical question is whether SERCA2a gene therapy predisposes to increased sarcoplasmic reticulum calcium (SR Ca2+) leak, cellular triggered activity and ventricular arrhythmias in the failing heart.
Methods and Results
We studied the influence of SERCA2a gene therapy upon ventricular arrhythmogenesis in a rat chronic heart failure model. ECG telemetry studies revealed a significant antiarrhythmic effect of SERCA2a gene therapy with reduction of both spontaneous and catecholamine-induced arrhythmias in vivo. SERCA2a gene therapy also reduced susceptibility to reentry arrhythmias in ex vivo programmed electrical stimulation studies. Subcellular Ca2+ homeostasis and spontaneous SR Ca2+ leak characteristics were measured in failing cardiomyocytes transfected in vivo with a novel AAV9.SERCA2a vector. SR Ca2+ leak was reduced following SERCA2a gene therapy, with reversal of the greater spark mass observed in the failing myocytes, despite normalisation of SR Ca2+ load. SERCA2a reduced ryanodine receptor phosphorylation, thereby resetting SR Ca2+ leak threshold, leading to reduced triggered activity in vitro. Both indirect effects of reverse remodelling and direct SERCA2a effects appear to underlie the antiarrhythmic action.
SERCA2a gene therapy stabilizes SR Ca2+ load, reduces ryanodine receptor phosphorylation and decreases SR Ca2+ leak, reduces cellular triggered activity in vitro and spontaneous and catecholamine-induced ventricular arrhythmias in vivo in failing hearts. SERCA2a gene therapy did not therefore predispose to arrhythmias, and may even represent a novel antiarrhythmic strategy in heart failure.
PMCID: PMC3119354  PMID: 21406682
Arrhythmia; Gene Therapy; Calcium; Heart Failure; SERCA2a
19.  Circumcision 
PMCID: PMC2814274  PMID: 20132716
20.  Child neglect: what does it have to do with general practice? 
PMCID: PMC2801781  PMID: 20040162
21.  ‘A coal face option’: GPs' perspectives on the rise in antidepressant prescribing 
The British Journal of General Practice  2009;59(566):e299-e307.
Levels of antidepressant prescribing have dramatically increased in Western countries in the last two decades.
To explore GPs' views about, and explanations for, the increase in antidepressant prescribing in Scotland between 1995 and 2004.
Qualitative, interview study.
General practices, Scotland.
GPs in 30 practices (n = 63) purposively selected to reflect a range of practice characteristics and levels of antidepressant prescribing.
Interviews with GPs were taped and transcribed. Analysis followed a Framework Approach.
GPs offered a range of explanations for the rise in antidepressant prescribing in Scotland. Few doctors thought that the incidence of depression had increased, and many questioned the appropriateness of current levels of prescribing. A number of related factors were considered to have contributed to the increase. These included: the success of campaigns to raise awareness of depression; a willingness among patients to seek help; and the perceived safety of selective serotonin reuptake inhibitors, making it easier for GPs to manage depression in primary care. Many GPs believed that unhappiness, exacerbated by social deprivation and the breakdown of traditional social structures, was being ‘medicalised’ inappropriately.
Most antidepressant prescriptions in Scotland are issued by GPs, and current policy aims to reduce levels of prescribing. To meet this aim, GPs' prescribing behaviour needs to change. The findings suggest that GPs see themselves as responders to, rather than facilitators of, change and this has obvious implications for initiatives to reduce prescribing.
PMCID: PMC2734377  PMID: 19761658
depression; drugs; mental health; qualitative research; primary care
22.  Predicting which people with psychosocial distress are at risk of becoming dependent on state benefits: analysis of routinely available data 
Objectives To examine whether there was significant variation in levels of claiming incapacity benefit across general practices. To establish whether it is possible to identify people with mental health problems who are more at risk of becoming dependent on state benefits for long term health problems based on their general practice consulting behaviour.
Design Interrogation of routinely available data in the Scottish Health Surveys and the British Household Panel Survey.
Setting Scotland and the United Kingdom.
Participants Respondents to the Scottish Health Surveys in 1995, 1998, and 2003 (7932, 12 939 and 11 472 respondents, respectively). Respondents to the British Household Panel Survey, 1991-2007 (more than 5000 households).
Main outcome measures Intracluster correlation coefficient for probability of work incapacity by general practice. Caseness according to the general health questionnaire (GHQ-12) and frequency of consultation with general practitioner in years before and after starting to claim incapacity benefit.
Results There was a small and non-significant amount of variation across general practices in Scotland in rate of claims for incapacity benefit after adjustment for other explanatory variables (intracluster correlation coefficient 0.01, P=0.135). There was a significant increase in rates of GHQ-12 caseness from two years before the start of claiming incapacity benefit (odds ratio 1.6, 95% confidence interval 1.3 to 1.9) and an increase in frequent consultation with a general practitioner from three years before the start of claiming incapacity benefit (1.8, 1.3 to 2.4). People with GHQ-12 caseness showed a significant increase in frequent consultations with a general practitioner from two years before the start of claiming incapacity benefit (2.1, 1.4 to 3.2).
Conclusions There was no variation in levels of claiming incapacity benefit across general practices in Scotland after adjustment for differences in population characteristics and so initiatives targeted at practices with high levels are unlikely to be effective. People with mental health problems who are likely to have problems remaining in work can be identified up to three years before they transit on to long term benefits related to ill health.
PMCID: PMC2923293  PMID: 20716597
23.  Effects of metoprolol and carvedilol on pre‐existing and new onset diabetes in patients with chronic heart failure: data from the Carvedilol Or Metoprolol European Trial (COMET) 
Heart  2007;93(8):968-973.
β Blocker treatment may worsen glucose metabolism.
To study the development of new onset diabetes in a large cohort of patients with heart failure treated with either metoprolol or carvedilol.
Prospective and retrospective analysis of a controlled clinical trial.
Multinational multicentre study.
3029 patients with chronic heart failure.
Randomly assigned treatment with carvedilol (n = 1511, target dose 50 mg daily) or metoprolol tartrate (n = 1518, target dose 100 mg daily).
Diabetic events (diabetic coma, peripheral gangrene, diabetic foot, decreased glucose tolerance or hyperglycaemia) and new onset diabetes (clinical diagnosis, repeated high random glucose level or glucose lowering drugs) were assessed in 2298 patients without diabetes at baseline. Diabetic events occurred in 122/1151 (10.6%) patients in the carvedilol group and 149/1147 (13.0%) patients in the metoprolol group (hazard ratio (HR) = 0.78; 95% confidence interval (CI) 0.61 to 0.99; p = 0.039). New onset diabetes was diagnosed in 119/1151 (10.3%) v 145/1147 (12.6%) cases in the carvedilol and metoprolol treatment groups (HR = 0.78, CI 0.61 to 0.997; p = 0.048), respectively. Patients with diabetes at baseline had an increased mortality compared with non‐diabetic subjects (45.3% v 33.9%; HR = 1.45, CI 1.28 to 1.65). Both diabetic and non‐diabetic subjects at baseline had a similar reduction in mortality with carvedilol compared with metoprolol (RR = 0.85; CI 0.69 to 1.06 and RR = 0.82; CI 0.71 to 0.94, respectively).
A high prevalence and incidence of diabetes is found in patients with heart failure over a course of 5 years. New onset diabetes is more likely to occur during treatment with metoprolol than during treatment with carvedilol.
PMCID: PMC1994413  PMID: 17237130
β adrenergic receptor antagonists; carvedilol; diabetes mellitus; heart failure; metoprolol
24.  Years-needed-to-treat to add 1 year of life: a new metric to estimate treatment effects in randomized trials 
European Journal of Heart Failure  2009;11(3):256-263.
A standard metric to estimate absolute treatment effects is numbers-needed-to-treat (NNT), which implicitly assumes that all benefits reverse at trial-end. However, in-trial survival benefits typically do not reverse until long after trial-end, so that NNT will substantially underestimate lifetime benefits.
Methods and results
We developed a new concept, years-needed-to-treat (YNT) to add 1 year of life, that quantifies the expected average life expectancy for two treatments including the estimated years of life remaining post-trial. Numbers-needed-to-treat and YNT were calculated in the COMET trial, in which carvedilol vs. metoprolol tartrate resulted in 17% lower mortality over 4.8 years. A multivariate Cox model was used to predict survival. Remaining years of life were estimated using the mortality-life-table method. At trial-end, survival was 9% higher in the carvedilol arm. Assuming that patients remained on the same therapy post-trial, the average total years of life for carvedilol vs. metoprolol were 10.63 ± 0.19 vs. 9.48 ± 0.18 (P < 0.0001) or 1.15 (95% confidence interval 0.64–1.66) additional years of life. The YNT was 9.2, indicating that 9.2 person-years of treatment added 1 person-year of life, compared with NNT of 59.
Compared with NNT, the YNT method more accurately accounts for potential long-term benefits of interventions in randomized trials.
PMCID: PMC2645057  PMID: 19164422
Heart failure; Prognostication; Outcomes; Epidemiology; Gompertz; Beta-blocker; Number-needed-to-treat; Years-needed-to-treat
25.  Factors influencing variation in prescribing of antidepressants by general practices in Scotland 
The prescribing of antidepressants has been rising dramatically in developed countries.
As part of an investigation into the reasons for the rise and variation in the prescribing of antidepressants, this study aimed to describe, and account for, the variation in an age–sex standardised rate of antidepressant prescribing between general practices.
Design of study
Cross-sectional study involving analyses of routinely available data.
A total of 983 Scottish general practices.
Age–sex standardised prescribing rates were calculated for each practice. Univariate and multivariate regression analyses were undertaken to examine how the variation in prescribing was related to population, GP, and practice characteristics at individual practice level.
There was a 4.6-fold difference between the first and ninth deciles of antidepressant prescribing, standardised for registered patients' age and sex composition. The multivariate model explained 49.4% of the variation. Significantly higher prescribing than expected was associated with more limiting long-term illness (highly correlated with deprivation and the single most influential factor), urban location, and a greater proportion of female GPs in the practices. Significantly lower prescribing than expected was associated with single-handed practices, a higher than average list size, a greater proportion of GP partners born outside the UK, remote rural areas, a higher proportion of patients from minority ethnic groups, a higher mean GP age, and availability of psychology services. None of the quality-of-care indicators investigated was associated with prescribing levels.
Almost half of the variation in the prescription of antidepressants can be explained using population, GP, and practice characteristics. Initiatives to reduce the prescribing of antidepressants should consider these factors to avoid denying appropriate treatment to patients in some practices.
PMCID: PMC2629838  PMID: 19192364
antidepressants; clinical practice variation; family practice; Scotland

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