Trends in long-term prescribing of dependence forming medicines

Using patient-level primary care data to estimate the extent to which antidepressant medicines are prescribed to people continuously for long periods of time. Aim This descriptive research used patient-level primary care data to estimate the extent to which antidepressant medicines are prescribed to people continuously for long periods of time. The study also drew on survey data and data on the number of prescriptions dispensed. Findings - The number of antidepressant prescriptions dispensed each year in England doubled between 2008 and 2018 - Survey data show that the proportion of adults reporting use of antidepressants in the past year increased in the 1990s, and again between 2007 and 2014 - The average length of time that antidepressants are continuously prescribed to people for has increased over time. - Some types of antidepressants (for example, tricyclics and other antidepressants) tend to be prescribed for longer periods than other types (such as SSRIs). - In 2014, one in twelve prescribing periods for tricyclics and other antidepressants lasted for three years or more Methods The analyses in this report are descriptive and show the overall prevalence of long-term prescribing in each year. We used a sample of around 50,000 patients prescribed at least one antidepressant medicine between 2000 and 2017. This was drawn from the Clinical Practice Research Datalink (CPRD). The CPRD contains data about prescriptions issued by GPs (including the length and size of prescription) and characteristics of the patients prescribed to (such as their age, sex, and area where they live). Medicines were grouped for analysis into: tricyclics, selective serotonin reuptake inhibitors (SSRIs), and other ADMs. The length of individual prescriptions and continuous prescribing periods were derived using information on consultation dates, the quantity of tablets prescribed, and the numeric daily dose

The impact of early life skills on later outcomes

In this report we assess the evidence on the long-run associations between early social, emotional and cognitive skills (focusing on measures before age six) and a range of later outcomes. We summarize these skills under the umbrella term of ‘life skills’ and provide a taxonomy, or descriptive model, of specific skill sets. Regarding outcomes, we focus on educational attainment, employment, income, health, and wellbeing. There are three elements to this report: 1. A definition and taxonomy of key social, emotional, and cognitive skills 2. A literature review of evidence on the relationship between childhood social, emotional and cognitive skills and a range of later outcomes 3. New analysis of the British Cohort Study (BCS) on the long-run benefits and predictive power of early skills, using assessments made at age five and linking them to outcomes later in life, up to age 42

The South Asian genome

Genetics of disease Microarrays Variant genotypes Population genetics Sequence alignment AllelesThe genetic sequence variation of people from the Indian subcontinent who comprise one-quarter of the world's population, is not well described. We carried out whole genome sequencing of 168 South Asians, along with whole-exome sequencing of 147 South Asians to provide deeper characterisation of coding regions. We identify 12,962,155 autosomal sequence variants, including 2,946,861 new SNPs and 312,738 novel indels. This catalogue of SNPs and indels amongst South Asians provides the first comprehensive map of genetic variation in this major human population, and reveals evidence for selective pressures on genes involved in skin biology, metabolism, infection and immunity. Our results will accelerate the search for the genetic variants underlying susceptibility to disorders such as type-2 diabetes and cardiovascular disease which are highly prevalent amongst South Asians.Whole genome sequencing to discover genetic variants underlying type-2 diabetes, coronary heart disease and related phenotypes amongst Indian Asians. Imperial College Healthcare NHS Trust cBRC 2011-13 (JS Kooner [PI], JC Chambers)

The rise of dentine hypersensitivity and tooth wear in an ageing population

Our understanding of the aetiology of dentine hypersensitivity (DH) has changed dramatically over the past few decades. It is no longer an enigma, but other problems exist. The prevalence of DH in the world and in particular in the UK is increasing, predominately due to increases in tooth wear and the erosive dietary intake in the younger population. DH is increasingly reported in all age groups and is shown to provide clinical indication of an active erosive tooth wear. As the population ages and possibly retain teeth for longer, the likelihood of tooth wear and DH could increase. This paper describes the prevalence, aetiology, diagnosis and management of DH in relation to tooth wear, which work together through a surface phenomenon. The aim is to raise awareness of the conditions and to help inform a prevention strategy in an ageing population, which starts from younger age groups to reduce disease into older age

Regulatory role of CD8(+ )T lymphocytes in bone marrow eosinophilopoiesis

BACKGROUND: There is a growing body of evidence to suggest that CD8(+ )T lymphocytes contribute to local allergen-induced eosinophilic inflammation. Since bone marrow (BM) responses are intricately involved in the induction of airway eosinophilia, we hypothesized that CD8(+ )T lymphocytes, as well as CD4(+ )T lymphocytes, may be involved in this process. METHODS: Several approaches were utilized. Firstly, mice overexpressing interleukin-5 (IL-5) in CD3(+ )T lymphocytes (NJ.1638; CD3(IL-5+ )mice) were bred with gene knockout mice lacking either CD4(+ )T lymphocytes (CD4(-/-)) or CD8(+ )T lymphocytes (CD8(-/-)) to produce CD3(IL-5+ )knockout mice deficient in CD4(+ )T lymphocytes (CD3(IL-5+)/CD4(-/-)) and CD8(+ )T lymphocytes (CD3(IL-5+)/CD8(-/-)), respectively. Secondly, CD3(+), CD4(+ )and CD8(+ )T lymphocytes from naïve CD3(IL-5+ )and C57BL/6 mice were adoptively transferred to immunodeficient SCID-bg mice to determine their effect on BM eosinophilia. Thirdly, CD3(IL-5+), CD3(IL-5+)/CD8(-/- )and CD3(IL-5+)/CD4(-/- )mice were sensitized and allergen challenged. Bone marrow and blood samples were collected in all experiments. RESULTS: The number of BM eosinophils was significantly reduced in CD3(IL-5+)/CD8(-/- )mice compared to CD3(IL-5+ )mice and CD3(IL-5+)/CD4(-/- )mice. Serum IL-5 was significantly higher in CD3(IL-5+)/CD4(-/- )mice compared to CD3(IL-5+ )mice but there was no difference in serum IL-5 between CD3(IL-5+)/CD4(-/- )and CD3(IL-5+)/CD8(-/- )mice. Adoptive transfer of CD8(+), but not CD4(+ )T lymphocytes from naïve CD3(IL-5+ )and C57BL/6 mice restored BM eosinophilia in immunodeficient SCID-bg mice. Additionally, allergen challenged CD3(IL-5+)/CD8(-/- )mice developed lower numbers of BM eosinophils compared to CD3(IL-5+ )mice and CD3(IL-5+)/CD4(-/- )mice. CONCLUSION: This study shows that CD8(+ )T lymphocytes are intricately involved in the regulation of BM eosinophilopoiesis, both in non-sensitized as well as sensitized and allergen challenged mice

The role of ALOX5AP, LTA4H and LTB4R polymorphisms in determining baseline lung function and COPD susceptibility in UK smokers

<p>Abstract</p> <p>Background</p> <p>We have previously shown evidence that polymorphisms within genes controlling leukotriene B₄(LTB₄) production (<it>ALOX5AP </it>and <it>LTA4H</it>) are associated with asthma susceptibility in children. Evidence also suggests a potential role of LTB₄in COPD disease mechanisms including recruitment of neutrophils to the lung. The aim of the current study was to see if these SNPs and those spanning the receptor genes for LTB₄(<it>LTB4R1 </it>and <it>LTB4R2</it>) influence baseline lung function and COPD susceptibility/severity in smokers.</p> <p>Methods</p> <p>Eight <it>ALOX5AP</it>, six <it>LTA4H </it>and six <it>LTB4R </it>single nucleotide polymorphisms (SNPs) were genotyped in a UK Smoking Cohort (n = 992). Association with baseline lung function (FEV₁and FEV₁/FVC ratio) was determined by linear regression. Logistic regression was used to compare smoking controls (n = 176) with spirometry-defined COPD cases (n = 599) and to more severe COPD cases (GOLD stage 3 and 4, n = 389).</p> <p>Results</p> <p>No association with <it>ALOX5AP</it>, <it>LTA4H </it>or <it>LTB4R </it>survived correction for multiple testing. However, we showed modest association with <it>LTA4H </it>rs1978331C (intron 11) with increased FEV₁(p = 0.029) and with increased FEV₁/FVC ratio (p = 0.020).</p> <p>Conclusions</p> <p>These data suggest that polymorphisms spanning <it>ALOX5AP</it>, <it>LTA4H </it>and the <it>LTB4R </it>locus are not major determinants of baseline lung function in smokers, but provide tentative evidence for <it>LTA4H </it>rs1978331C (intron 11) in determining baseline FEV₁and FEV₁/FVC ratio in Caucasian Smokers in addition to our previously identified role in asthma susceptibility.</p

CSL311, a novel, potent, therapeutic monoclonal antibody for the treatment of diseases mediated by the common beta chain of the IL-3, GM-CSF and IL-5 receptors

The β common-signaling cytokines interleukin (IL)-3, granulocyte-macrophage colony stimulating factor (GM-CSF) and IL-5 stimulate pro-inflammatory activities of haematopoietic cells via a receptor complex incorporating cytokine-specific α and shared β common (βc, CD131) receptor. Evidence from animal models and recent clinical trials demonstrate that these cytokines are critical mediators of the pathogenesis of inflammatory airway disease such as asthma. However, no therapeutic agents, other than steroids, that specifically and effectively target inflammation mediated by all 3 of these cytokines exist. We employed phage display technology to identify and optimize a novel, human monoclonal antibody (CSL311) that binds to a unique epitope that is specific to the cytokine-binding site of the human βc receptor. The binding epitope of CSL311 on the βc receptor was defined by X-ray crystallography and site-directed mutagenesis. CSL311 has picomolar binding affinity for the human βc receptor, and at therapeutic concentrations is a highly potent antagonist of the combined activities of IL-3, GM-CSF and IL-5 on primary eosinophil survival in vitro. Importantly, CSL311 inhibited the survival of inflammatory cells present in induced sputum from human allergic asthmatic subjects undergoing allergen bronchoprovocation. Due to its high potency and ability to simultaneously suppress the activity of all 3 β common cytokines, CSL311 may provide a new strategy for the treatment of chronic inflammatory diseases where the human βc receptor is central to pathogenesis. The coordinates for the βc/CSL311 Fab complex structure have been deposited with the RCSB Protein Data Bank (PDB 5DWU).Con Panousis, Urmi Dhagat, Kirsten M. Edwards, Veronika Rayzman, Matthew P. Hardy, Hal Braley, Gail M. Gauvreau, Timothy R. Hercus, Steven Smith, Roma Sehmi, Laura McMillan, Mara Dottore, Barbara J. McClure, Louis J. Fabri, Gino Vairo, Angel F Lopez, Michael W. Parker, Andrew D. Nash, Nicholas J. Wilson, Michael J. Wilson and Catherine M. Owczare

A genome-wide association study in Europeans and South Asians identifies five new loci for coronary artery disease

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Fractional Flow Reserve and Instantaneous Wave-Free Ratio as Predictors of the Placebo-Controlled Response to Percutaneous Coronary Intervention in Stable Single-Vessel Coronary Artery Disease: Physiology-Stratified Analysis of ORBITA

BACKGROUND: There are no data on how fractional flow reserve (FFR) and instantaneous wave-free ratio (iFR) are associated with the placebo-controlled efficacy of percutaneous coronary intervention (PCI) in stable single-vessel coronary artery disease. METHODS: We report the association between prerandomization invasive physiology within ORBITA (Objective Randomised Blinded Investigation With Optimal Medical Therapy of Angioplasty in Stable Angina), a placebo-controlled trial of patients who have stable angina with angiographically severe single-vessel coronary disease clinically eligible for PCI. Patients underwent prerandomization research FFR and iFR assessment. The operator was blinded to these values. Assessment of response variables, treadmill exercise time, stress echocardiography score, symptom frequency, and angina severity were performed at prerandomization and blinded follow-up. Effects were calculated by analysis of covariance. The ability of FFR and iFR to predict placebo-controlled changes in response variables was tested by using regression modeling. RESULTS: Invasive physiology data were available in 196 patients (103 PCI and 93 placebo). At prerandomization, the majority had Canadian Cardiovascular Society class II or III symptoms (150/196, 76.5%). Mean FFR and iFR were 0.69±0.16 and 0.76±0.22, respectively; 97% had ≥1 positive ischemia tests. The estimated effect of PCI on between-arm prerandomization-adjusted total exercise time was 20.7 s (95% confidence interval [CI], -4.0 to 45.5; P=0.100) with no interaction of FFR (Pinteraction=0.318) or iFR (Pinteraction=0.523). PCI improved stress echocardiography score more than placebo (1.07 segment units; 95% CI, 0.70-1.44; P<0.00001). The placebo-controlled effect of PCI on stress echocardiography score increased progressively with decreasing FFR (Pinteraction<0.00001) and decreasing iFR (Pinteraction<0.00001). PCI did not improve angina frequency score significantly more than placebo (odds ratio, 1.64; 95% CI, 0.96-2.80; P=0.072) with no detectable evidence of interaction with FFR (Pinteraction=0.849) or iFR (Pinteraction=0.783). However, PCI resulted in more patient-reported freedom from angina than placebo (49.5% versus 31.5%; odds ratio, 2.47; 95% CI, 1.30-4.72; P=0.006) but neither FFR (Pinteraction=0.693) nor iFR (Pinteraction=0.761) modified this effect. CONCLUSIONS: In patients with stable angina and severe single-vessel disease, the blinded effect of PCI was more clearly seen by stress echocardiography score and freedom from angina than change in treadmill exercise time. Moreover, the lower the FFR or iFR, the greater the magnitude of stress echocardiographic improvement caused by PCI