Seasonal timing of fluorescence and photosynthetic yields at needle and canopy scales in evergreen needleleaf forests.

The seasonal timing and magnitude of photosynthesis in evergreen needleleaf forests (ENFs) has major implications for the carbon cycle and is increasingly sensitive to changing climate. Earlier spring photosynthesis can increase carbon uptake over the growing season or cause early water reserve depletion that leads to premature cessation and increased carbon loss. Determining the start and the end of the growing season in ENFs is challenging due to a lack of field measurements and difficulty in interpreting satellite data, which are impacted by snow and cloud cover, and the pervasive "greenness" of these systems. We combine continuous needle-scale chlorophyll fluorescence measurements with tower-based remote sensing and gross primary productivity (GPP) estimates at three ENF sites across a latitudinal gradient (Colorado, Saskatchewan, Alaska) to link physiological changes with remote sensing signals during transition seasons. We derive a theoretical framework for observations of solar-induced chlorophyll fluorescence (SIF) and solar intensity-normalized SIF (SIFrelative) under snow-covered conditions, and show decreased sensitivity compared with reflectance data (~20% reduction in measured SIF vs. ~60% reduction in near-infrared vegetation index [NIRv] under 50% snow cover). Needle-scale fluorescence and photochemistry strongly correlated (r2 = 0.74 in Colorado, 0.70 in Alaska) and showed good agreement on the timing and magnitude of seasonal transitions. We demonstrate that this can be scaled to the site level with tower-based estimates of LUEP and SIFrelative which were well correlated across all sites (r2 = 0.70 in Colorado, 0.53 in Saskatchewan, 0.49 in Alaska). These independent, temporally continuous datasets confirm an increase in physiological activity prior to snowmelt across all three evergreen forests. This suggests that data-driven and process-based carbon cycle models which assume negligible physiological activity prior to snowmelt are inherently flawed, and underscores the utility of SIF data for tracking phenological events. Our research probes the spectral biology of evergreen forests and highlights spectral methods that can be applied in other ecosystems.

Use and persistence of single and multiple inhaler triple therapy prescribed for patients with COPD in France: a retrospective study on THIN database (OPTI study).

INTRODUCTION: From 2018 single inhaler triple therapy (SITT) became available in France to treat moderate-to-severe chronic obstructive pulmonary disease (COPD). Given its simplified inhaler use compared with multiple inhaler triple therapy (MITT), this therapeutic option has the potential to offer benefit in terms of improved persistence and adherence. Given the lack of real-world evidence of the effectiveness of triple therapy, this study was designed to evaluate the use of MITT and SITT in France and compare persistence. METHODS: A retrospective cohort study was performed. Patients with COPD who initiated triple therapy between 1 July 2017 and 31 December 2019 were included from The Health Improvement Network, a large electronic medical database in France, which includes pharmacy data. A 60-day treatment gap defined discontinuation and thereby persistence. RESULTS: A total of 3134 patients initiated triple therapy for COPD in the study period, among them 485 with SITT. In 2019, the rate of use of SITT was 28.2%. The mean age (67.3 years) and sex (44.2% female) of patients initiating triple therapy was similar between MITT and SITT, and most patients had escalated from dual therapy (84.1%). However, SITT was more frequently initiated by a pulmonologist (59.8%) and a higher prevalence of comorbid asthma was observed for SITT (47.0% vs 37.9%). Persistence was assessed among patients who did not discontinue after a single dispensation of triple therapy (n=1674). Median persistence was 181 days for SITT and 135 days for MITT, and the covariate-adjusted HR for persistence was 1.47 (p<0.001) and the estimated persistence at 1 year was 33% for SITT compared with 18% for MITT. DISCUSSION: This study suggests that persistence was higher for the patients treated with SITT compared with MITT in France. Moreover, most patients initiated with triple therapy were previously treated with dual therapy and had exacerbations in the previous year.

Vertical gradients in photosynthetic physiology diverge at the latitudinal range extremes of white spruce.

Light availability drives vertical canopy gradients in photosynthetic functioning and carbon (C) balance, yet patterns of variability in these gradients remain unclear. We measured light availability, photosynthetic CO2  and light response curves, foliar C, nitrogen (N) and pigment concentrations, and the photochemical reflectance index (PRI) on upper and lower canopy needles of white spruce trees (Picea glauca) at the species' northern and southern range extremes. We combined our photosynthetic data with previously published respiratory data to compare and contrast canopy C balance between latitudinal extremes. We found steep canopy gradients in irradiance, photosynthesis and leaf traits at the southern range limit, but a lack of variation across canopy positions at the northern range limit. Thus, unlike many tree species from tropical to mid-latitude forests, high latitude trees may not require vertical gradients of metabolic activity to optimize photosynthetic C gain. Consequently, accounting for self-shading is less critical for predicting gross primary productivity at northern relative to southern latitudes. Northern trees also had a significantly smaller net positive leaf C balance than southern trees suggesting that, regardless of canopy position, low photosynthetic rates coupled with high respiratory costs may ultimately constrain the northern range limit of this widely distributed boreal species.

Remote sensing tracks daily radial wood growth of evergreen needleleaf trees.

Relationships between gross primary productivity (GPP) and the remotely sensed photochemical reflectance index (PRI) suggest that time series of foliar PRI may provide insight into climate change effects on carbon cycling. However, because a large fraction of carbon assimilated via GPP is quickly returned to the atmosphere via respiration, we ask a critical question-can PRI time series provide information about longer term gains in aboveground carbon stocks? Here we study the suitability of PRI time series to understand intra-annual stem-growth dynamics at one of the world's largest terrestrial carbon pools-the boreal forest. We hypothesized that PRI time series can be used to determine the onset (hypothesis 1) and cessation (hypothesis 2) of radial growth and enable tracking of intra-annual tree growth dynamics (hypothesis 3). Tree-level measurements were collected in 2018 and 2019 to link highly temporally resolved PRI observations unambiguously with information on daily radial tree growth collected via point dendrometers. We show that the seasonal onset of photosynthetic activity as determined by PRI time series was significantly earlier (p < .05) than the onset of radial tree growth determined from the point dendrometer time series which does not support our first hypothesis. In contrast, seasonal decline of photosynthetic activity and cessation of radial tree growth was not significantly different (p > .05) when derived from PRI and dendrometer time series, respectively, supporting our second hypothesis. Mixed-effects modeling results supported our third hypothesis by showing that the PRI was a statistically significant (p < .0001) predictor of intra-annual radial tree growth dynamics, and tracked these daily radial tree-growth dynamics in remarkable detail with conditional and marginal coefficients of determination of 0.48 and 0.96 (for 2018) and 0.43 and 0.98 (for 2019), respectively. Our findings suggest that PRI could provide novel insights into nuances of carbon cycling dynamics by alleviating important uncertainties associated with intra-annual vegetation response to climate change.

Early-stage Mycosis Fungoides: Epidemiology and Prognosis.

Most patients with mycosis fungoides are diagnosed with early-stage disease. However, prevalence of early-stage disease is unknown, and evidence of its burden is scarce. The aim of this study is to estimate the prevalence of early-stage mycosis fungoides, how long patients live with early-stage disease and to characterise these patients. Data were obtained from 4 key publications and from US cancer registries (Surveillance, Epidemiology and End Results Program; SEER). The derived incidence of early-stage mycosis fungoides was 0.26/100,000 (UK), 0.29/100,000 (US) and 0.38/100,000 (US-SEER) and the prevalence was 4.8/100,000 (UK), 5.2/100,000 (US) and 6.6/100,000 (US-SEER). Early-stage disease may last for 18 years. From SEER registries, 3,132 were diagnosed at early stage (mostly stage IA). Median age at diagnosis was 58 years. Compared with stage IA, the relative risk of death was 1.3 for stage IB and 3.5 for stage IIA. We confirm the rarity of early-stage mycosis fungoides, a differential prognosis and the potential for elevated burden of disease.

Gout and the risk of advanced chronic kidney disease in the UK health system: a national cohort study.

OBJECTIVE: Evaluate the association between gout and risk of advanced chronic kidney disease (CKD). DESIGN: Retrospective matched cohort study. SETTING: UK Clinical Practice Research Datalink. PARTICIPANTS: The analysis included data for 68 897 patients with gout and 554 964 matched patients without gout. Patients were aged ≥18 years, registered at UK practices, had ≥12 months of clinical data and had data linked with Hospital Episode Statistics. Patients were excluded for history of advanced CKD, juvenile gout, cancer, HIV, tumour lysis syndrome, Lesch-Nyhan syndrome or familial Mediterranean fever. PRIMARY AND SECONDARY OUTCOME MEASURES: Advanced CKD was defined as first occurrence of: (1) dialysis, kidney transplant, diagnosis of end-stage kidney disease (ESKD) or stage 5 CKD (diagnostic codes in Read system or International Classification of Diseases, Tenth Revision); (2) estimated glomerular filtration rate (eGFR) <10 mL/min/1.73 m²; (3) doubling of serum creatinine from baseline and (4) death associated with CKD. RESULTS: Advanced CKD incidence was higher for patients with gout (8.54 per 1000 patient-years; 95% CI 8.26 to 8.83) versus without gout (4.08; 95% CI 4.00 to 4.16). Gout was associated with higher advanced CKD risk in both unadjusted analysis (HR, 2.00; 95% CI 1.92 to 2.07) and after adjustment (HR, 1.29; 95% CI 1.23 to 1.35). Association was strongest for ESKD (HR, 2.13; 95% CI 1.73 to 2.61) and was present for eGFR <10 mL/min/1.73 m² (HR, 1.45; 95% CI 1.30 to 1.61) and serum creatinine doubling (HR, 1.13; 95% CI 1.08 to 1.19) but not CKD-associated death (HR, 1.14; 95% CI 0.99 to 1.31). Association of gout with advanced CKD was replicated in propensity-score matched analysis (HR, 1.23; 95% CI 1.17 to 1.29) and analysis limited to patients with incident gout (HR, 1.28; 95% CI 1.22 to 1.35). CONCLUSIONS: Gout is associated with elevated risk of CKD progression. Future studies should investigate whether controlling gout is protective and reduces CKD risk.

Initiation and continuation of oral anticoagulant prescriptions for stroke prevention in non-valvular atrial fibrillation: A cohort study in primary care in France.

BACKGROUND: Oral anticoagulants are prescribed in non-valvular atrial fibrillation for stroke prevention; however, little is known about the current management of anticoagulation in France, particularly given the availability of non-vitamin K antagonist oral anticoagulants in recent years. AIMS: To describe the characteristics of patients prescribed oral anticoagulants, and assess treatment persistence in French primary care. METHODS: We conducted a cohort study of patients with non-valvular atrial fibrillation, who were newly prescribed oral anticoagulants between 1 January 2014 and 31 January 2016, using French primary care data (IMS Longitudinal Patient Database). Adjusting for baseline characteristics, risk of non-persistence (switch or discontinuation) was compared using Cox regression. RESULTS: Of 4111 patients, 1710 were newly prescribed vitamin K antagonists, 1257 rivaroxaban, 744 apixaban and 400 dabigatran. The median age was 76 years, and 57.5% were male. History of hypertension was the most common co-morbidity (68.1%). Compared with vitamin K antagonists, non-persistence was higher with rivaroxaban (hazard ratio: 1.28; 95% confidence interval: 1.13-1.45) and dabigatran (hazard ratio: 1.42; 95% confidence interval: 1.20-1.69) and similar with apixaban (hazard ratio: 1.12; 95% confidence interval: 0.96-1.32). CONCLUSIONS: Non-persistence (treatment discontinuation or switch) with vitamin K antagonists was lower than with rivaroxaban and dabigatran in French primary care; however, non-persistence with the newest drug, apixaban, was similar to vitamin K antagonists. Larger studies with longer follow-up are needed to support these findings. This study is registered on ClinicalTrials.gov (NCT02488421).

Rationale and design of the long-Term rIsk, clinical manaGement, and healthcare Resource utilization of stable coronary artery dISease in post-myocardial infarction patients (TIGRIS) study.

The long-term progression of coronary artery disease as defined by the natural disease course years after a myocardial infarction (MI) is an important but poorly studied area of clinical research. The long-Term rIsk, clinical manaGement, and healthcare Resource utilization of stable coronary artery dISease in post-myocardial infarction patients (TIGRIS) study was designed to address this knowledge gap by evaluating patient management and clinical outcomes following MI in different regions worldwide. TIGRIS (ClinicalTrials.gov Identifier: NCT01866904) is a multicenter, observational, prospective, longitudinal study enrolling patients with history of MI 1 to 3 years previously and high risk of developing atherothrombotic events in a general-practice setting. The primary objective of TIGRIS is to evaluate clinical events (time to first occurrence of any event from the composite cardiovascular endpoint of MI, unstable angina with urgent revascularization, stroke, or death from any cause), and healthcare resource utilization associated with hospitalization for these events (hospitalization duration and procedures) during follow-up. Overall, 9225 patients were enrolled between June 2013 and November 2014 and are being followed in 369 different centers worldwide. This will allow for the description of regional differences in patient characteristics, risk profiles, medical treatment patterns, clinical outcomes, and healthcare resource utilization. Patients will be followed for up to 3 years. Here we report the rationale, design, patient distribution, and selected baseline characteristics of the TIGRIS study. TIGRIS will describe real-world management, quality of life (self-reported health), and healthcare resource utilization for patients with stable coronary artery disease ≥1 year post-MI.

Oral anticoagulant persistence in patients with non-valvular atrial fibrillation: A cohort study using primary care data in Germany.

This study examined characteristics and treatment persistence among patients prescribed oral anticoagulants (OACs) for stroke prevention in non-valvular atrial fibrillation (NVAF). We identified 15,244 patients (51.8% male, 72.7% aged ≥70) with NVAF and no prior OAC therapy who were prescribed apixaban (n = 1,303), rivaroxaban (n = 5,742), dabigatran (n = 1,622) or vitamin-K antagonists (VKAs, n = 6,577) between 1-Dec-2012 and 31-Oct-2014 in German primary care (IMS® Disease Analyzer). We compared OAC persistence using Cox regression over patients' entire follow-up and using a data-driven time-partitioned approach (before/after 100 days) to handle non-proportional hazards. History of stroke risk factors (stroke/transient ischaemic attack [TIA] 15.2%; thromboembolism 14.1%; hypertension 84.3%) and high bleeding risk (HAS-BLED score≥3 68.4%) was common. Apixaban-prescribed patients had more frequent history of stroke/TIA (19.7%) and high bleeding risk (72.6%) than other OACs. 12-month persistence rates were: VKA 57.5% (95% confidence interval (CI) 56.0-59.0%), rivaroxaban 56.6% (54.9-58.2%), dabigatran 50.1% (47.2-53.1%), apixaban 62.9% (58.8-67.0%). Over entire follow-up, compared to VKA, non-persistence was similar with apixaban (adjusted hazard ratio 1.08, 95% CI 0.95-1.24) but higher with rivaroxaban (1.21, 1.14-1.29) and dabigatran (1.53, 1.40-1.68). Using post-hoc time-partitioned approach: in first 100 days, non-persistence was higher with apixaban (1.37, 1.17-1.59), rivaroxaban (1.41, 1.30-1.53) and dabigatran (1.91, 1.70-2.14) compared to VKA. Compared to apixaban, rivaroxaban non-persistence was similar (1.03, 0.89-1.20), dabigatran was higher (1.39, 1.17-1.66). After 100 days, apixaban non-persistence was lower than VKA (0.66, 0.52-0.85); rivaroxaban (0.97, 0.87-1.07) and dabigatran (1.10, 0.95-1.28) were similar to VKA. Furthermore, rivaroxaban (1.46, 1.13-1.88) and dabigatran (1.67, 1.26-2.19) non-persistence was higher than apixaban. This study describes real-world observations on OAC use, particularly early apixaban use following approval for NVAF, in Germany. We identified potential differential OAC prescribing and higher persistence with apixaban than other OACs after 100 days' treatment. Larger studies are needed with longer follow-up to establish long-term patterns.

Identifying rare diseases using electronic medical records: the example of allergic bronchopulmonary aspergillosis.

PURPOSE: The purpose of the study is to evaluate whether primary care electronic medical records (EMRs) from patients with severe asthma can be used to identify allergic bronchopulmonary aspergillosis (ABPA) cases. METHODS: This cross-sectional feasibility study was conducted in adults with active and severe asthma registered with the Clinical Practice Research Datalink. A set of keywords flagged terms potentially indicative of ABPA in free-text comments of patients' EMRs to produce a grid on the basis of keywords' hit or miss. The grid was examined for occurrence and concurrence of keywords to discern patterns of concurrence potentially indicative of an underlying diagnosis of ABPA. RESULTS: The analyses included 3 653 169 free-text items from 21 054 patients. In total, 52 patients (0.25%) had at least one mention of 'ABPA' in their medical record; 67% of these patients also had a mention of 'aspergillus/aspergillosis', 54% of 'bronchiectasis', 42% of 'itraconazole' and 62% of 'IgE'. The term 'aspergillus/aspergillosis' occurred with a proportion of 1.84% (N = 387); 9% of these patients also had a mention of 'ABPA', and the remaining 91% were potential additional cases of ABPA. From the observed concurrence of keywords, we were able to devise a potential algorithm to identify cases with varying degrees of specificity. CONCLUSIONS: This study suggests that analysis of free text within asthmatic patients' EMRs may be used to identify potential cases of ABPA. This could be an efficient approach to identify rare conditions and to quantify their potential burden. © 2017 The Authors. Pharmacoepidemiology & Drug Safety Published by John Wiley & Sons Ltd.

Longer-term oral antiplatelet use in stable post-myocardial infarction patients: Insights from the long Term rIsk, clinical manaGement and healthcare Resource utilization of stable coronary artery dISease (TIGRIS) observational study.

OBJECTIVE: To describe contemporary patient characteristics and treatment patterns, including antithrombotic management, of post-myocardial infarction (MI) stable coronary artery disease (CAD) patients at high atherothrombotic risk from different geographical regions. METHODS: Patients ≥50years with prior MI 1-3years ago and ≥1 risk factor (age ≥65years, diabetes, 2nd prior MI >1yr ago, multivessel CAD, creatinine clearance 15-<60ml/min) were enrolled by 369 physicians (96% cardiologists) in 25 countries (2013-14) in the prospective TIGRIS study (NCT01866904). RESULTS: 9225 patients were enrolled (median 1.8years) post-MI: 52% with prior ST-elevation MI, median age 67years, 24% women, 67% Caucasian, 55% had ≥2 additional qualifying risk factors, 14% current smokers, 67% overweight/obese, 34% with blood pressure ≥140/90mmHg. 81% underwent percutaneous coronary intervention (PCI; 66% with drug-eluting stents) for the index MI. 75% of patients had been discharged on dual antiplatelet therapy (DAPT; acetylsalicylic acid [ASA]+ADP receptor inhibitor [ADPri]), mainly clopidogrel (75%). 63% had discontinued antiplatelet treatment (60% ADPri) around 1year, most commonly by physician recommendation (90%). At enrolment, 97% were taking an antithrombotic drug, most commonly ASA (88%), with 27% on DAPT (median duration 1.6years); continued DAPT >1year was highest (39%) in Asia-Pacific and lowest (12%) in Europe. CONCLUSIONS: Despite guideline recommendations, 1 in 4 post-MI patients did not receive DAPT for ~1year. In contrast to guideline recommendations supporting newer ADPris, clopidogrel was mainly prescribed. Prior to recent RCT data supporting DAPT >1year post-MI/PCI, >1 in 4 patients have continued on DAPT, though with substantial international variability.

Molecular Basis for Cohesin Acetylation by Establishment of Sister Chromatid Cohesion N-Acetyltransferase ESCO1.

Protein acetylation is a prevalent posttranslational modification that is regulated by diverse acetyltransferase enzymes. Although histone acetyltransferases (HATs) have been well characterized both structurally and mechanistically, far less is known about non-histone acetyltransferase enzymes. The human ESCO1 and ESCO2 paralogs acetylate the cohesin complex subunit SMC3 to regulate the separation of sister chromatids during mitosis and meiosis. Missense mutations within the acetyltransferase domain of these proteins correlate with diseases, including endometrial cancers and Roberts syndrome. Despite their biological importance, the mechanisms underlying acetylation by the ESCO proteins are not understood. Here, we report the X-ray crystal structure of the highly conserved zinc finger-acetyltransferase moiety of ESCO1 with accompanying structure-based mutagenesis and biochemical characterization. We find that the ESCO1 acetyltransferase core is structurally homologous to the Gcn5 HAT, but contains unique additional features including a zinc finger and an ∼40-residue loop region that appear to play roles in protein stability and SMC3 substrate binding. We identify key residues that play roles in substrate binding and catalysis, and rationalize the functional consequences of disease-associated mutations. Together, these studies reveal the molecular basis for SMC3 acetylation by ESCO1 and have broader implications for understanding the structure/function of non-histone acetyltransferases.

Early real-world evidence of persistence on oral anticoagulants for stroke prevention in non-valvular atrial fibrillation: a cohort study in UK primary care.

OBJECTIVES: To examine the characteristics and persistence in patients newly initiated with oral anticoagulants (OACs) for stroke prevention in non-valvular atrial fibrillation (NVAF). DESIGN: Cohort study in Clinical Practice Research Datalink. SETTING: UK primary care. PARTICIPANTS: 15 242 patients with NVAF newly prescribed apixaban, rivaroxaban, dabigatran or vitamin K antagonists (VKAs) between 1 December 2012 and 31 October 2014. 13 089 patients were OAC naïve. OUTCOME MEASURES: Patient characteristics and risk of non-persistence compared to apixaban using Cox regression models over the entire follow-up and using a time-partitioned approach to handle non-proportional hazards. RESULTS: Among the OAC naïve patients, VKAs were most common (78.1%, n=10 218), followed by rivaroxaban (12.1%, n=1589), dabigatran (5.7%, n=741) and apixaban (4.1%, n=541). High baseline stroke risk (CHA2DS2VASc ≥2) ranged from 80.2% (dabigatran) to 88.4% (apixaban and rivaroxaban). History of stroke and bleeding was the highest among apixaban (23.7% and 31.6%) and lowest among VKA patients (15.9% and 27.5%). Across the entire follow-up period, adjusting for differences in characteristics, there was no evidence of a difference in non-persistence between VKA and apixaban (HR 0.92 (95% CI 0.68 to 1.23)). Non-persistence was higher with dabigatran (HR 1.67 (1.20 to 2.32)) and rivaroxaban (HR 1.41 (1.02 to 1.93)) than apixaban. Using the partitioned approach, non-persistence was lower with VKA (HR 0.33 (0.22 to 0.48)), and higher with dabigatran (HR 1.65 (1.08 to 2.52)) compared to apixaban in the first 2 months of follow-up. After 2 months, non-persistence was higher with VKA (HR 1.70 (1.08 to 2.66)) and dabigatran (HR 2.10 (1.30 to 3.41)). Pooling OAC naïve and experienced patients, non-persistence was also higher with rivaroxaban compared to apixaban after 2 months of follow-up (HR 1.69 (1.19 to 2.39)). CONCLUSIONS: Observed differential prescribing of OACs can result in channelling bias in comparative effectiveness research. Persistence patterns changed over follow-up time, but there are indications of improved persistence rates with apixaban over other OACs in the UK. A larger study with longer follow-up is needed to corroborate findings. This study is registered on ClinicalTrials.gov (NCT02488421).

Antihyperglycaemic treatment patterns, observed glycaemic control and determinants of treatment change among patients with type 2 diabetes in the United Kingdom primary care: a retrospective cohort study.

BACKGROUND: The initial treatment strategy for patients with type 2 diabetes includes lifestyle change recommendations. When patients are not successful in controlling their blood glucose levels through healthier lifestyle pharmaceutical agents are recommended. The objective of this study is to identify determinants of initial treatment change following initiation of non-insulin antihyperglycaemic treatment (OAD) for UK patients with type 2 diabetes. METHODS: A retrospective cohort study using primary care data from the Clinical Practice Research Datalink between January 2006 and February 2011. Each patient had an OAD prescription. The main treatment pattern outcomes were discontinuation, switching, augmentation and initiation of insulin. Glycaemic control was assessed using HbA1c. RESULTS: 63,060 patients initiated OAD therapy 2006-2010 and 3.4% were prescribed insulin during follow-up. 26% with at least four years of follow-up remained on the initial treatment. Metformin dominated (90%) in UK primary care. Around 75% had a record of HbA1c testing prior to initiating therapy. On initiating OAD, half the patients had HbA1c values >65 mmol/mol and one quarter >80 mmol/mol. The initial values of HbA1c were reduced after 12 months and remained stable. There were 15%-18% of patients whose values increased since initiating OAD. Increased baseline HbA1c is associated with increased chance of augmentation and decreased chance of discontinuation. HbA1c values at 1 year were associated with a three-fold increase in the chance of augmentation, 130% increase in the chance of switching and 14% increase in the chance of discontinuation with each 10 mmol/mol increase. Following initiation of OAD, HbA1c was reduced by an average of 16 mmol/mol during the first year. CONCLUSION: There are patients for whom glycaemic control worsens and a majority remained above the recommended level, suggesting an unmet need despite the availability of many OAD.

Prevalence of gastrointestinal stromal tumour (GIST) in the United Kingdom at different therapeutic lines: an epidemiologic model.

BACKGROUND: The prevalence of patients with gastrointestinal stromal tumourgst (GIST) who fail currently available treatments imatinib and sunitinib (third-line treatment-eligible GIST) is unknown, but is expected to be below an ultra-orphan disease threshold of 2/100,000 population used in England and Wales. Our study was designed to estimate the prevalence and absolute number of UK patients with unresectable/metastatic GIST at first-, second- and eventually third-line treatment. METHODS: Our open population model estimates the probability that the prevalence of UK third-line treatment-eligible GIST patients will remain under the ultra-orphan disease threshold. Model parameters for incidence, proportion of unresectable/metastatic disease and survival estimates for GIST patients were obtained from a targeted literature review and a UK cancer register. The robustness of the results was checked through differing scenarios taking extreme values of the input parameters. RESULTS: The base-case scenario estimated a prevalence of third-line treatment-eligible GIST of 1/100,000 and a prevalence count of 598 with a 99.9% likelihood of being below the ultra-orphan disease threshold. The extreme scenarios, one-way and probabilistic sensitivity analyses and threshold analysis confirmed the robustness of these results. CONCLUSIONS: The prevalence of third-line treatment-eligible GIST is very low and highly likely below the ultra-orphan disease threshold.

Treatment patterns and therapy effectiveness in psoriasis patients initiating biologic therapy in England.

OBJECTIVE: To describe biologic treatment patterns and effectiveness among patients with psoriasis who initiated biologic therapy. METHODS: A chart review was conducted for 169 patients with psoriasis initiating biologic treatment between 1 July 2005 and 30 June 2009 from six dermatology clinics. Severity was measured by the Psoriasis Area and Severity Index (PASI) at baseline and time of treatment change. Biologic treatment patterns in the 12 months following initiation (discontinuation, switching, dose increase, and persistence) were collected. RESULTS: Mean (SD) PASI score at initiation was 18.4 (7.8). Eighteen percent of patients discontinued biologic use, 12% switched, and 7% increased biologic dose within the first 12 months. Patients persistent on initial biologic therapy (64%) achieved a mean PASI score of 3.8 at 12 months; 69% achieved PASI ≥75. For patients who discontinued due to lack of effectiveness, mean PASI score was 22.6; no patient reached PASI ≥75. Among patients who switched, mean PASI was 15.7 (0% PASI ≥75) at the time of switch. In those who increased their dose, mean PASI score was 9.1 (43% reached PASI ≥75) at the time of dose increase. CONCLUSIONS: A large proportion (36%) of patients changed or discontinued biologic therapy within the first year. These patients experienced limited PASI response, if any, suggesting an unmet need for this population.

Treatment and referral patterns for psoriasis in United Kingdom primary care: a retrospective cohort study.

BACKGROUND: In the UK, referrals to specialists are initiated by general practitioners (GPs). Study objectives were to estimate the incidence of diagnosed psoriasis in the UK and identify factors associated with GP referrals to dermatologists. METHODS: Newly diagnosed patients with psoriasis were identified in The Health Improvement Network (THIN) database between 01 July 2007-31 Oct 2009. Incidence of diagnosed psoriasis was calculated using the number of new psoriasis patients in 2008 and the mid-year total patient count for THIN in 2008. A nested case-control design and conditional logistic regression were used to identify factors associated with referral. RESULTS: Incidence rate of diagnosed adult psoriasis in 2008 was 28/10,000 person-years. Referral rate to dermatologists was 18.1 (17.3-18.9) per 100 person-years. In the referred cohort (N=1,950), 61% were referred within 30 days of diagnosis and their median time to referral was 0 days from diagnosis. For those referred after 30 days (39%, median time to referral: 5.6 months), an increase in the number of GP visits prior to referral increased the likelihood of referral (OR=1.87 95% CI:1.73-2.01). A prescription of topical agents such as vitamin D3 analogues 30 days before referral increased the likelihood of being referred (OR=4.67 95% CI: 2.78-7.84), as did corticosteroids (OR=2.45 95% CI: 1.45-4.07) and tar products (OR=1.95 95% CI: 1.02-3.75). CONCLUSIONS: Estimates of the incidence of diagnosed adult psoriasis, referral rates to dermatologists, and characteristics of referred patients may assist in understanding the burden on the UK healthcare system and managing this population in primary and secondary care.

Evaluation of varenicline as an aid to smoking cessation in UK general practice - a THIN database study.

OBJECTIVES: Varenicline is a licensed smoking cessation medication in the EU, USA and many other countries worldwide. This study was designed to assess its effectiveness in a UK general practice setting. METHODS: The main outcome measure was the rate of smoking cessation, defined as the seven-day point prevalence after six months from starting varenicline. Varenicline users were identified from records in The Health Improvement Network (THIN) database. A questionnaire on smoking cessation was sent to patients who commenced treatment close to the selection date (six months prior to the date of questionnaire dispatch). RESULTS: The response rate was 26.4%: 193 responses were received. Ninety percent had previously attempted to stop smoking and 87.4% had used nicotine replacement therapy during the previous attempt to stop smoking. The overall smoking cessation rate was 49.5%. There was a strong association between the duration of varenicline treatment and smoking cessation. Patients who reported using varenicline for 9-12 weeks were 11 times more likely to stop smoking than those who completed less than two weeks of treatment. There was some evidence that patients with a longer history of smoking were less likely to stop. No association was observed between smoking cessation and: previous number of cigarettes smoked per day; number of previous attempts to stop smoking; or motivations for stopping. CONCLUSIONS: Varenicline appeared to be a useful pharmacological aid to smoking cessation in a general practice setting. The observed effectiveness was similar to the efficacy estimates from previously reported clinical trials. However, the response rate was lower than expected and responders tended to be older, more likely to suffer from chronic obstructive pulmonary disease and to live in more affluent areas than non-responders. Responses were self-reported and not clinically validated therefore recall bias may be an issue.

The importance of defining periods of complete mortality reporting for research using automated data from primary care.

PURPOSE: To define periods of acceptable mortality reporting in primary care and to demonstrate through examples the implication for research using automated medical data. METHODS: Annual death counts were obtained for each primary care practice participating in The Health Improvement Network "THIN" (UK). Expected counts were calculated from national death rates, accounting for the practice's age/sex structure. The standardized mortality ratio (SMR) was calculated with 95% confidence intervals (CI). A visual review process was undertaken to assign the year from which the practice had acceptable mortality reporting (AMR). The process involved reviewer pairs who were blinded to each other's decisions. Patterns of death reporting were checked. The AMR year was applied as a filter to THIN data to assess its impact on the SMR. RESULTS: For most practices the SMR was relatively stable and the AMR year was easily identified with 86% agreement between the blinded reviewer pairs. Applying the AMR to THIN removed under-reporting of death. However, the total computerized follow-up reduced from 37 to 32 million patient-years. Problematic death recording patterns included some practices keeping only live patient records when converting their software systems thereby creating 'immortal periods' prior to this moment, and peaks occurring when practices updated the vital status of their patients' records. CONCLUSIONS: This is the first time that an external standard has been used to assess completeness of mortality in automated primary care data. The resulting AMR year provides a natural filter for research and avoids biases associated with 'immortal periods', record updating and under-reporting.

Quantitative assessment of the gastrointestinal and cardiovascular risk-benefit of celecoxib compared to individual NSAIDs at the population level.

PURPOSE: To estimate the net cardiovascular (CV) (coronary heart disease, stroke, congestive heart failure), and gastrointestinal (GI) (peptic ulcer complications) risk-benefit public health impact of the use of celecoxib compared to non-selective NSAIDs in the arthritis population. METHODS: We applied discrete event simulation models to data from the US National Health Surveys, CV risk-prediction models from the Framingham Heart Study, and population-based studies. Models took into account the multifactorial effect of risk factors, comorbidity, and competing risk of mortality. We simulated the natural history of CV and GI disease in the U.S. arthritis population over 1 year, through the individual baseline cardiovascular and gastrointestinal risk profile. This model was modified with relative risks associated with the use of each treatment. The mean number of events was estimated for each end-point in each model: natural history, celecoxib, diclofenac, ibuprofen, naproxen. The number of events for celecoxib was compared with each NSAID. RESULTS: The evaluation included 1% of the U.S. population with arthritis. Celecoxib, when applied to 100 000 patients over 1 year, resulted in 570 (range from sensitivity analysis: 440-691), 226 (124-313), and 746 (612-868) fewer ulcer complications than diclofenac, ibuprofen, and naproxen, respectively. There were 20 (16-25), 8 (4-12), and 27 (22-32) fewer deaths from ulcer complications, respectively. No increase in cardiovascular events or all cause mortality was observed for celecoxib versus the other individual NSAIDs. CONCLUSION: Results from these simulations suggest a gastrointestinal benefit for celecoxib not offset by increased cardiovascular events or mortality. The methodology used here provides a risk-benefit assessment framework for evaluating the public heath impact of drugs.