Oral corticosteroid prescription patterns for asthma in France, Germany, Italy and the UK.

Oral corticosteroids (OCS) are used to manage asthma exacerbations and severe, uncontrolled asthma, but OCS use is associated with adverse effects. We aimed to describe the patterns of OCS use in the real-world management of patients with asthma in western Europe.We used electronic medical records from databases in France, Germany, Italy and the United Kingdom from July 2011 through February 2018. Patients aged ≥12 years with an asthma diagnosis, at least one non-OCS asthma medication within ±6 months of diagnosis, and available data ≥6 months prior to and ≥90 days after cohort entry were included. High OCS use was defined as OCS ≥450 mg prescribed in a 90-day window during follow-up. Baseline characteristics and OCS use during follow-up were described overall and by OCS use status.Of 702 685 patients with asthma, 14-44% were OCS users and 6-9% were high OCS users at some point during follow-up. Annual prevalence of high OCS use across all countries was ∼3%. High OCS users had a mean of between one and three annual OCS prescriptions, with an average daily OCS dosage of 1.3-2.2 mg. For patients who continued to meet the high-use definition, daily OCS exposure was generally stable at 5.5-7.5 mg for ≥2 years, increasing the risk of adverse effects.Our study demonstrates that OCS use is relatively common across the four studied European countries. Data from this study may provide decisive clinical insights to inform primary care physicians and specialists involved in the management of severe, uncontrolled asthma.

Observational safety study of specific outcomes after trivalent cell culture seasonal influenza vaccination (Optaflu® ) among adults in THIN database of electronic UK primary healthcare records.

PURPOSE: To investigate the safety of trivalent seasonal influenza vaccine (TIVc) (Optaflu® ), the first cell culture seasonal trivalent influenza vaccine available in Europe. METHODS: Codes and unstructured text in adult electronic healthcare records (The Health Improvement Network) were searched for a TIVc brand name or batch number and possible outcomes within a 3 month pre- to 6 month post-TIVc exposure study period (2012-2015). The outcomes were severe allergic reactions, Bell's palsy, convulsions, demyelination, paresthesia, noninfectious encephalitis, neuritis (optic and brachial), vasculitis, inflammatory bowel disease, and thrombocytopenia. Risk periods were defined based on biologically plausible time frame postvaccination when an outcome caused by the vaccine might be expected to occur. Possible outcomes were adjudicated against outcome specific case definitions and a date of onset assigned by using electronic and other medical records. Observed (risk period) to expected (outside risk and preexposure periods) rate ratios, postexposure incidence, and plots of time from exposure to outcome were reported. RESULTS: Sixteen of 1011 events from 4578 exposures fulfilled a primary case definition and had a date of onset during the study period. Three were in observed time. The observed-to-expected rate ratios were (3.3, 95% CI 0.3, 31.7) for convulsions and (1.5, 95% CI 0.2, 14.9) for thrombocytopenia with 1 outcome each in observed time. There was 1 incident inflammatory bowel disease in observed, but none in expected, time. CONCLUSION: The small sample size restricts interpretation; however, no hypothesis of an increased risk of a study outcome was generated. Adjudication of events against case definitions to reduce misclassification of onset and outcomes allowed use of precise risk periods. KEY POINTS This observational study did not generate a hypothesis of an association between the first cell-culture seasonal influenza vaccination available in the European Union and any of the study outcomes (severe allergic reactions, Bell's palsy, convulsions, demyelination, paresthesia, noninfectious encephalitis, neuritis [optic and brachial], vasculitis, inflammatory bowel disease [IBD], and thrombocytopenia). The small sample size limits interpretation of the results. The review of each possible outcome identified from electronic healthcare records against case definitions was included to minimize misclassification of time and outcomes and allow the use of precise risk-periods in an observed-to-expected within cohort analysis. Plots of time from exposure to outcome were included to assess the risk windows.

Immune-Related Toxicity in NSCLC: Current State-of-the-Art and Emerging Clinical Challenges.

Immune checkpoint inhibitors have become standard-of-care for the treatment of NSCLC; however, their use brings with it the risk of a unique set of inflammatory side effects, termed immune-related adverse events (irAEs). The recognition, diagnosis, and management of irAEs have become essential to clinical practice, with the potential for high-grade toxicities affecting treatment decision-making. This manuscript provides a state-of-the-art review of irAEs as they pertain to patients with NSCLC, by summarizing the common and severe toxicities of the standard immune checkpoint inhibitor regimens and clinical treatment settings relevant to this disease and future directions.

Atopic dermatitis in West Highland white terriers is associated with a 1.3-Mb region on CFA 17.

Canine atopic dermatitis (AD) is an allergic inflammatory skin disease that shares similarities with AD in humans. Canine AD is likely to be an inherited disease in dogs and is common in West Highland white terriers (WHWTs). We performed a genome-wide association study using the Affymetrix Canine SNP V2 array consisting of over 42,800 single nucleotide polymorphisms, on 35 atopic and 25 non-atopic WHWTs. A gene-dropping simulation method, using SIB-PAIR, identified a projected 1.3 Mb area of association (genome-wide P = 6 × 10(-5) to P = 7 × 10(-4)) on CFA 17. Nineteen genes on CFA 17, including 1 potential candidate gene (PTPN22), were located less than 0.5 Mb from the interval of association identified on the genome-wide association analysis. Four haplotypes within this locus were differently distributed between cases and controls in this population of dogs. These findings suggest that a major locus for canine AD in WHWTs may be located on, or in close proximity to an area on CFA 17.

Prevalence of congenital hereditary sensorineural deafness in Australian Cattle Dogs and associations with coat characteristics and sex.

BACKGROUND: Congenital hereditary sensorineural deafness (CHSD) occurs in many dog breeds, including Australian Cattle Dogs. In some breeds, CHSD is associated with a lack of cochlear melanocytes in the stria vascularis, certain coat characteristics, and potentially, abnormalities in neuroepithelial pigment production. This study investigates phenotypic markers for CHSD in 899 Australian Cattle Dogs. RESULTS: Auditory function was tested in 899 Australian Cattle Dogs in family groups using brainstem auditory evoked response testing. Coat colour and patterns, facial and body markings, gender and parental hearing status were recorded.Deafness prevalence among all 899 dogs was 10.8% with 7.5% unilaterally deaf, and 3.3% bilaterally deaf, and amongst pups from completely tested litters (n = 696) was 11.1%, with 7.5% unilaterally deaf, and 3.6% bilaterally deaf.Univariable and multivariable analyses revealed a negative association between deafness and bilateral facial masks (odds ratio 0.2; P ≤ 0.001). Using multivariable logistic animal modelling, the risk of deafness was lower in dogs with pigmented body spots (odds ratio 0.4; P = 0.050).No significant associations were found between deafness and coat colour.Within unilaterally deaf dogs with unilateral facial masks, no association was observed between the side of deafness and side of mask. The side of unilateral deafness was not significantly clustered amongst unilaterally deaf dogs from the same litter. Females were at increased risk of deafness (odds ratio from a logistic animal model 1.9; P = 0.034) after adjusting for any confounding by mask type and pigmented body spots. CONCLUSIONS: Australian Cattle Dogs suffer from CHSD, and this disease is more common in dogs with mask-free faces, and in those without pigmented body patches. In unilaterally deaf dogs with unilateral masks, the lack of observed association between side of deafness and side of mask suggests that if CHSD is due to defects in molecular pigment pathways, the molecular control of embryonic melanoblast migration from ectoderm to skin differs from control of migration from ectoderm to cochlea. In Australian Cattle Dogs, CHSD may be more common in females.

Clinical utility of anti-interleukin 5 monoclonal therapy in asthma using a national, centralised, outcome-based system of drug access.

INTRODUCTION: Interleukin 5 (IL-5) inhibitors are an important therapeutic advance in the management of severe, refractory, eosinophilic asthma. However, their utilisation should be targeted to maximise their benefits. This study used multisite, centralised, national data collected over 18 months to perform an observational integrated, retrospective, cohort study of selection criteria for initiation and continuation of IL-5 inhibitor treatment in Ireland. MATERIALS/PATIENTS AND METHODS: We used data from 230 patients who were given anti-IL-5 monoclonal therapy (reslizumab, mepolizumab or benralizumab) in Ireland between 2018 and 2020. Reimbursement of these drugs in Ireland requires fulfilling eligibility criteria defined by the Acute Hospitals Drugs Management Programme with continued reimbursement requiring ongoing submission of clinical data demonstrating clinical effectiveness. RESULTS: IL-5 inhibitor use for 18 months was associated with a total reduction in asthma-associated hospital admissions of 108 (p=0.036) and in non-hospital exacerbations of 85 in 18 months (p=0.014). Respiratory-associated GP visits were reduced from 637 in 12 months to 89 at 6 months and 210 at 18 months of treatment (p<0.001). Oral corticosteroid requirement was reduced or stopped entirely (p<0.001). Subgroup analysis of one site replicated these results and showed a significant reduction in the Asthma Control Questionnaire Score (p<0.001) CONCLUSIONS: Selected patients continued on IL-5 treatment to 18 months had significantly reduced exacerbations, GP visits, oral corticosteroid use and asthma-associated hospitalisations. These results show that anti-IL-5 therapy, in carefully selected and monitored patients with asthma, results in significant improvements in clinical outcomes in a real-world setting.

A randomised controlled trial of ion-exchange water softeners for the treatment of eczema in children.

BACKGROUND: Epidemiological studies and anecdotal reports suggest a possible link between household use of hard water and atopic eczema. We sought to test whether installation of an ion-exchange water softener in the home can improve eczema in children. METHODS AND FINDINGS: This was an observer-blind randomised trial involving 336 children (aged 6 months to 16 years) with moderate/severe atopic eczema. All lived in hard water areas (≥200 mg/l calcium carbonate). Participants were randomised to either installation of an ion-exchange water softener plus usual eczema care, or usual eczema care alone. The primary outcome was change in eczema severity (Six Area Six Sign Atopic Dermatitis Score, SASSAD) at 12 weeks, measured by research nurses who were blinded to treatment allocation. Analysis was based on the intent-to-treat population. Eczema severity improved for both groups during the trial. The mean change in SASSAD at 12 weeks was -5.0 (20% improvement) for the water softener group and -5.7 (22% improvement) for the usual care group (mean difference 0.66, 95% confidence interval -1.37 to 2.69, p = 0.53). No between-group differences were noted in the use of topical corticosteroids or calcineurin inhibitors. CONCLUSIONS: Water softeners provided no additional benefit to usual care in this study population. Small but statistically significant differences were found in some secondary outcomes as reported by parents, but it is likely that such improvements were the result of response bias, since participants were aware of their treatment allocation. A detailed report for this trial is also available at http://www.hta.ac.uk. TRIAL REGISTRATION: Current Controlled Trials ISRCTN71423189 Please see later in the article for the Editors' Summary.

High-throughput lectin magnetic bead array-coupled tandem mass spectrometry for glycoprotein biomarker discovery.

Alterations in protein glycosylation occur during development and progression of many diseases, hence glycomics and glycoproteomics have emerged as important tools in glycobiomarker discovery. High-throughput glycan profiling can now be achieved with the recent developments in MS-based techniques. To enable identification and rapid monitoring of glycosylation changes in serum proteins, we developed a semi-automated high-throughput glycoprotein biomarker discovery platform termed lectin magnetic bead array-coupled tandem mass spectrometry (LeMBA-MS) which includes (i) effective single-step serum glycoprotein isolation using a panel of 20 individual lectin-coated magnetic beads in microplate format, (ii) on-bead trypsin digestion, and (iii) nanoLC-MS/MS with lectin exclusion list. With use of appropriate sequence databases, LeMBA-MS can detect glycosylation changes regardless of the species. By spiking known amounts of titrated ovalbumin to a serum sample, we report nanomolar sensitivity, and linearity of response of LeMBA-MS using concanavalin A-coupled beads. Neuraminidase treatment led to reduction of binding to sialic acid-binding lectins. Interestingly, we found that desialylation caused increased binding of haptoglobin and hemopexin to mannose-specific lectins, pointing to the importance of identifying a signature of lectin-binding. High-throughput LeMBA-MS to generate glycosylation signatures will facilitate glycobiomarker discovery. LeMBA can be coupled to down-stream detection platforms for validation, making it a truly versatile platform.

IgE responsiveness to Dermatophagoides farinae in West Highland white terrier dogs is associated with region on CFA35.

Immunoglobulin E (IgE)-mediated hypersensitivity against environmental allergens, commonly including Dermatophagoides farinae, is associated with atopic diseases in both humans and dogs. We have recently identified a family of clinically healthy West Highland white terriers (WHWTs) with high-serum D. farinae-IgE levels. In this study, we investigated the genetic mechanism controlling IgE responsiveness in dogs by performing a genome-wide association study (GWAS) using the Affymetrix V2 Dog SNP array in 31 high-IgE and 24 low-IgE responder WHWTs. A gene-dropping simulation method, using SIB-PAIR software, showed significant allelic association between serum D. farinae-specific IgE levels and a 2.3-Mb area on CFA35 (best empirical P = 1 × 10(-5)). A nearby candidate gene, CD83, encodes a protein which has important immunological functions in antigen presentation and regulation of humoral immune responses. We sequenced this gene in 2 high-IgE responders and 2 low-IgE responders and identified an intronic polymorphic repeat sequence with a predicted functional effect, but the association was insufficient to explain the GWAS association signal in this population (P = 1 × 10(-3)). Further studies are necessary to investigate the significance of these findings for IgE responsiveness and atopic disease in the dog.

ADAMTS17 mutation associated with primary lens luxation is widespread among breeds.

Primary lens luxation (PLL) is a well-recognized, painful and potentially blinding inherited ocular condition in dogs. We screened PLL-affected dogs of 30 different breeds, to identify those which carried a previously described c.1473+1 G>A mutation in ADAMTS17 that is associated with PLL in Miniature Bull terriers, Lancashire Heelers, and Jack Russell terriers. This ADAMTS17 mutation was identified in PLL-affected dogs from 14 additional breeds. PLL-affected dogs from some breeds (most notably the Shar pei and the Brittany spaniel) did not carry the G1473+1A ADAMTS17 mutation, indicating they must suffer from a genetically distinct form of the condition. We also estimated the frequency of this ADAMTS17 mutation in some of the breeds. Our findings indicate the mutation segregates in a large number of different breeds of dog, many of which are terriers or breeds with terrier co-ancestry, but some of which have more diverse origins. Our results also indicate that the mutation is present at high frequency within most of the breeds in which it segregates. In the miniature bull terrier breed estimates of mutation frequency ranged from 0.27 to 0.39, corresponding to 7.3-15.2% PLL-affected dogs in this breed. We also identified an increased risk of PLL associated with heterozygosity at ADAMTS17, suggesting that carriers carry a low risk of developing PLL.

High allergen-specific serum immunoglobulin E levels in nonatopic West Highland white terriers.

Human and canine atopic dermatitis (AD) share an association with IgE specific to environmental allergens, but few studies have evaluated serum allergen-specific IgE in nonatopic dogs. This study compared serum allergen-specific IgE levels in 30 atopic and 18 nonatopic West Highland white terriers. Atopic dermatitis was confirmed using standard criteria. Nonatopic dogs were over 5 years of age and had no clinical signs or history of AD. Serum allergen-specific IgE levels were measured with Allercept(®) IgE ELISAs using a 48-allergen Australian panel. Positive reactions were defined as ≥150 ELISA absorbance units. Intradermal tests were performed in 16 atopic dogs, either at the time of or at various times prior to serum collection. In atopic dogs, the most common positive ELISA and intradermal test results were to Dermatophagoides farinae (11 of 30 dogs), but there were no statistically significant correlations between results from the two methods for any allergen. In nonatopic dogs, multiple high-positive ELISA reactions were reported to 45 of 48 allergens, most commonly D. farinae and Tyrophagus putrescentiae (17 of 18 dogs each). Positive ELISA results in nonatopic dogs were statistically significantly higher than those in atopic dogs for 44 of 48 allergens, including two allergens (D. farinae and Dermatophagoides pteronyssinus) commonly regarded as significant in canine AD. In conclusion, positive allergen-specific IgE ELISAs were not specific for canine AD, and high allergen-specific IgE levels were seen in nonatopic dogs. The clinical significance of this and whether it characterizes a protective phenotype is unclear.

Development and Validation of a Method to Estimate COPD Severity in Multiple Datasets: A Retrospective Study.

INTRODUCTION: Outcomes in chronic obstructive pulmonary disease (COPD) such as symptoms, hospitalisations and mortality rise with increasing disease severity. However, the heterogeneity of electronic medical records presents a significant challenge in measuring severity across geographies. We aimed to develop and validate a method to approximate COPD severity using the Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2011 classification scheme, which categorises patients based on forced expiratory volume in 1 s, hospitalisations and the modified Medical Research Council dyspnoea scale or COPD Assessment Test. METHODS: This analysis was part of a comprehensive retrospective study, including patients sourced from the IQVIA Medical Research Data [IMRD; incorporating data from The Health Improvement Network (THIN), a Cegedim database] and the Clinical Practice Research Datalink (CPRD) in the UK, the Disease Analyzer in Germany and the Longitudinal Patient Data in Italy, France and Australia. Patients in the CPRD with the complete set of information required to calculate GOLD 2011 groups were used to develop the method. Ordinal logistic models at COPD diagnosis and at index (first episode of triple therapy) were then used to validate the method to estimate COPD severity, and this was applied to the full study population to estimate GOLD 2011 categories. RESULTS: Overall, 4579 and 12,539 patients were included in the model at COPD diagnosis and at index, respectively. Models correctly classified 74.4% and 75.9% of patients into severe and non-severe categories at COPD diagnosis and at index, respectively. Age, gender, time between diagnosis and start of triple therapy, healthcare resource use, comorbid conditions and prescriptions were included as covariates. CONCLUSION: This study developed and validated a method to approximate disease severity based on GOLD 2011 categories that can potentially be used in patients without all the key parameters needed for this calculation.

Candidate Glycoprotein Biomarkers for Canine Visceral Hemangiosarcoma and Validation Using Semi-Quantitative Lectin/Immunohistochemical Assays.

Visceral hemangiosarcoma (HSA) is one of the more frequent cancers in dogs and has a high metastatic rate and poor prognosis, as clinical signs only become apparent in advanced stages of tumor development. In order to improve early and differential diagnostic capabilities and hence, prognosis for dogs with HSA, two types of biomarker are needed: a point-of-care diagnostic biomarker and a prognostic biomarker-preferentially based on samples obtained with minimally invasive methods. In this study, we applied a lectin magnetic bead array-coupled tandem mass spectrometry (LeMBA-MS/MS) workflow through discovery and validation phases to discover serum glycoprotein biomarker candidates for canine HSA. By this approach, we found that Datura stramonium (DSA), wheat germ agglutinin (WGA), Sambucus nigra (SNA), and Pisum sativum (PSA) lectins captured the highest number of validated candidate glycoproteins. Secondly, we independently validated serum LeMBA-MS/MS results by demonstrating the in situ relationship of lectin-binding with tumor cells. Using lectin-histochemistry and immunohistochemistry (IHC) for key proteins on tissues with HSA and semi-quantitation of the signals, we demonstrate that a combination of DSA histochemistry and IHC for complement C7 greatly increases the prospect of a more specific diagnosis of canine HSA.

Prescribing Pathways to Triple Therapy: A Multi-Country, Retrospective Observational Study of Adult Patients with Chronic Obstructive Pulmonary Disease.

INTRODUCTION: Maintenance treatment strategies in COPD recommend inhaled corticosteroid (ICS) + long-acting muscarinic antagonist (LAMA) + long-acting ß2-agonist (LABA) triple therapy after initial dual therapy. Little is known about how treatment pathways to triple therapy vary across countries in clinical practice. METHODS: This multi-country, retrospective cohort study (conducted 1 January 2005-1 May 2016) included patients with a COPD diagnosis, and (UK only) evidence of smoking history, or (France, Italy, Germany, and Australia) an indicator confirming COPD diagnosis, a first instance of triple therapy recorded during the study period and ≥ 12 months of data prior to this date. Treatment pathways to triple therapy were analyzed in patients whose first instance of triple therapy was on or after the initial COPD diagnosis. The proportion of patients who initiated triple therapy prior to initial COPD diagnosis was also estimated. Meta-analyses of the main results were performed. RESULTS: In 130,729 patients across all countries, mean age (standard deviation) ranged from 63.4 (10.4) years (Germany) to 69.8 (9.9) years (Italy), and median time (interquartile range) from initial COPD diagnosis to first prescription of triple therapy ranged from 16.9 (5.7-36.2) months (Australia) to 42.5 (13.9-87.4) months (UK). ICS + LABA was the most common treatment pathway prior to triple therapy in the UK, Germany, and Italy (27.3%-31.6%); no previous maintenance therapy prior to triple therapy was the most common pathway in France and Australia (32.5% and 37.9%, respectively). Meta-analyses provided a pooled estimate of 20.4% (95% confidence interval: 13.8%-29.1%) for the proportion of patients initiating triple therapy at or before initial COPD diagnosis. CONCLUSIONS: In this retrospective cohort study, treatment pathways to triple therapy were diverse within and between countries. The differing impact of treatments may affect quality of life and disease control in patients with COPD. Further analyses should investigate factors influencing pathways to triple therapy.

Prescribing Pathways to Triple Therapy: A Retrospective Observational Study of Adults with Chronic Obstructive Pulmonary Disease in the UK.

Purpose: Treatment guidance for chronic obstructive pulmonary disease (COPD) recommends inhaled corticosteroid (ICS)+long-acting muscarinic antagonist+long-acting ß2-agonist (LABA) triple therapy for patients who experience recurrent exacerbations, persistent breathlessness, or exercise limitation on dual therapy. However, information is limited on pathways to triple therapy in the UK. Patients and Methods: A retrospective cohort study was conducted using de-identified patient-level data from UK primary care electronic medical records from January 1, 2005 to May 1, 2016. Data were included from patients who had their first triple therapy regimen (index date) recorded during the study period and a minimum of 12 months' pre-index data. Treatment pathways to triple therapy were recorded, and the proportion of patients on triple therapy before their COPD diagnosis was determined. Adherence to triple therapy was estimated using the proportion of days covered (PDC). Results: After applying eligibility criteria, 82,300 patients were included, with a mean age at COPD diagnosis of 64.7 years. The major treatment pathway (27.9%) was the first initiation of ICS+LABA prior to triple therapy. Following COPD diagnosis, the median time to triple therapy was approximately 3.5 years. The estimated mean adherence to triple therapy was 81.8% PDC. Multivariate analysis showed that the following groups were more likely to have received previous therapy prior to triple therapy: females (versus males), patients with asthma (versus those without asthma), severe COPD (versus those with non-severe COPD), or fewer exacerbations (versus those with more exacerbations). Conclusion: Treatment pathways to triple therapy in the UK are diverse, highlighting the need to better understand factors involved in clinical decision-making.

Evaluating glycaemic control in patients poorly controlled on oral antidiabetic drugs in real-world setting: Results from assessing the Appropriate Timing of Type 2 diAbetes INtensification (ATTAIN).

INTRODUCTION: Many patients with type 2 diabetes mellitus (DM) fail to achieve glycaemic control despite recommended treatment strategies to reduce glycated haemoglobin (HbA1c). This real-world retrospective cohort study compared HbA1c change and treatment patterns between those intensifying and not intensifying therapy with oral antidiabetic drugs (OADs). MATERIALS AND METHODS: Patients suboptimally controlled on OADs (>58 mmol/mol [>7.5%] or >64 mmol/mol [>8.0%] for high risk, index 1) were included from IQVIA Medical Research Data. Intensifiers within 12 months of index 1 were matched (1:1) to nonintensifiers. Primary outcomes were HbA1c change and proportion of participants achieving HbA1c targets 6 and 12 months post-index 2 (date of intensification [intensifiers] or pseudodate [nonintensifiers]). Therapy adherence was also assessed. RESULTS: A total of 10 832 participants (5539 intensifiers and 5293 nonintensifiers) were included. Mean HbA1c decrease from baseline to 6 months was -1.13% (intensifiers) vs -0.75% (nonintensifiers), with no substantial further change at 12 months. Cox proportional hazards (PH) analysis suggested a nearly 20% greater chance of target achievement at 6 months for intensifiers vs nonintensifiers (hazard ratio [HR]: 0.79 [95% confidence interval [CI]: 0.73-0.86]), which was similar at 12 months (HR: 0.80 [95% CI: 0.74-0.86]). Intensifiers tended towards greater adherence to baseline therapy (90% [standard deviation (SD): 14.9] vs nonintensifiers 87% [SD: 16.0]), which decreased following intensification. CONCLUSIONS: Significant reductions in HbA1c were evident at 6 months and were greater in intensifiers vs nonintensifiers. Little additional clinical benefit was seen 12 months postintensification. Despite good treatment adherence, many participants failed to achieve target HbA1c; actions beyond improved adherence are needed to improve suboptimal HbA1c.

Mapping of Diabetes Susceptibility Loci in a Domestic Cat Breed with an Unusually High Incidence of Diabetes Mellitus.

Genetic variants that are associated with susceptibility to type 2 diabetes (T2D) are important for identification of individuals at risk and can provide insights into the molecular basis of disease. Analysis of T2D in domestic animals provides both the opportunity to improve veterinary management and breeding programs as well as to identify novel T2D risk genes. Australian-bred Burmese (ABB) cats have a 4-fold increased incidence of type 2 diabetes (T2D) compared to Burmese cats bred in the United States. This is likely attributable to a genetic founder effect. We investigated this by performing a genome-wide association scan on ABB cats. Four SNPs were associated with the ABB T2D phenotype with p values <0.005. All exons and splice junctions of candidate genes near significant single-nucleotide polymorphisms (SNPs) were sequenced, including the genes DGKG, IFG2BP2, SLC8A1, E2F6, ETV5, TRA2B and LIPH. Six candidate polymorphisms were followed up in a larger cohort of ABB cats with or without T2D and also in Burmese cats bred in America, which exhibit low T2D incidence. The original SNPs were confirmed in this cohort as associated with the T2D phenotype, although no novel coding SNPs in any of the seven candidate genes showed association with T2D. The identification of genetic markers associated with T2D susceptibility in ABB cats will enable preventative health strategies and guide breeding programs to reduce the prevalence of T2D in these cats.

Evaluating Glycemic Control in Patients with Type 2 Diabetes Suboptimally Controlled on Basal Insulin: UK ATTAIN Real-World Study.

INTRODUCTION: This retrospective, observational cohort study evaluated the effect of therapy intensification on change in glycated hemoglobin (HbA1c) at 6 and 12 months post intensification in patients with type 2 diabetes (T2D) suboptimally controlled on basal insulin (BI) (i.e., HbA1c ≥ 7.5% [≥ 58 mmol/mol]). METHODS: Patients with T2D with suboptimal glycemic control using BI were identified from The Health Improvement Network (THIN) database. Patients who underwent therapy intensification (intensifiers) within 12 months of index 1 (the date of the first incidence of suboptimally controlled HbA1c) were matched (1:1) to patients who did not intensify therapy (non-intensifiers). Index 2 was the date of therapy intensification for intensifiers, or a pseudo date for non-intensifiers that resulted in the same duration from index 1 to index 2 as their matched intensifier patient. Primary outcomes were HbA1c change and proportion of patients achieving the HbA1c target at 6 and 12 months post index 2. RESULTS: A total of 1342 patients (n = 646 intensifiers; n = 696 non-intensifiers) were included in the analysis. At post index 2, mean HbA1c change was substantially greater at 6 months for intensifiers than for non-intensifiers (- 0.81% vs. - 0.35%), with no additional benefit at 12 months (- 0.81% vs. - 0.49%, respectively). Compared with non-intensifiers, a greater proportion of intensifiers achieved target HbA1c at 6 months (25.1% vs. 18.8%) and at 12 months (33.4% vs. 28.2%). CONCLUSIONS: Many real-world patients with T2D suboptimally controlled with BI do not have their therapy intensified. The results of this study suggest that in this patient population, therapy intensification achieves significant reductions in HbA1c at 6 months post intensification, with little additional clinical benefit at 12 months. This suggests that, for patients who fail to achieve their glycemic targets at 6 months, since no meaningful additional clinical benefit is observed at 12 months when continuing the same therapy, further therapy intensification or change should be promptly considered. FUNDING: This study and the Rapid Service Fees were funded by Sanofi. TRIAL REGISTRATION: 17THIN068.

Opioid use, postoperative complications, and implant survival after unicompartmental versus total knee replacement: a population-based network study.

BACKGROUND: There is uncertainty around whether to use unicompartmental knee replacement (UKR) or total knee replacement (TKR) for individuals with osteoarthritis confined to a single compartment of the knee. We aimed to emulate the design of the Total or Partial Knee Arthroplasty Trial (TOPKAT) using routinely collected data to assess whether the efficacy results reported in the trial translate into effectiveness in routine practice, and to assess comparative safety. METHODS: We did a population-based network study using data from four US and one UK health-care database, part of the Observational Health Data Sciences and Informatics network. The inclusion criteria were the same as those for TOPKAT; briefly, we identified patients aged at least 40 years with osteoarthritis who had undergone UKR or TKR and who had available data for at least one year prior to surgery. Patients were excluded if they had evidence of previous knee arthroplasty, knee fracture, knee surgery (except diagnostic), rheumatoid arthritis, infammatory arthropathies, or septic arthritis. Opioid use from 91-365 days after surgery, as a proxy for persistent pain, was assessed for all participants in all databases. Postoperative complications (ie, venous thromboembolism, infection, readmission, and mortality) were assessed over the 60 days after surgery and implant survival (as measured by revision procedures) was assessed over the 5 years after surgery. Outcomes were assessed in all databases, except for readmission, which was assessed in three of the databases, and mortality, which was assessed in two of the databases. Propensity score matched Cox proportional hazards models were fitted for each outcome. Calibrated hazard ratios (cHRs) were generated for each database to account for observed differences in control outcomes, and cHRs were then combined using meta-analysis. FINDINGS: 33 867 individuals who received UKR and 557 831 individuals who received TKR between Jan 1, 2005, and April 30, 2018, were eligible for matching. 32 379 with UKR and 250 377 with TKR were propensity score matched and informed the analyses. UKR was associated with a reduced risk of postoperative opioid use (cHR from meta-analysis 0·81, 95% CI 0·73-0·90) and a reduced risk of venous thromboembolism (0·62, 0·36-0·95), whereas no difference was seen for infection (0·85, 0·51-1·37) and readmission (0·79, 0·47-1·25). Evidence was insufficient to conclude whether there was a reduction in risk of mortality. UKR was also associated with an increased risk of revision (1·64, 1·40-1·94). INTERPRETATION: UKR was associated with a reduced risk of postoperative opioid use compared with TKR, which might indicate a reduced risk of persistent pain after surgery. UKR was associated with a lower risk of venous thromboembolism but an increased risk of revision compared with TKR. These findings can help to inform shared decision making for individuals eligible for knee replacement surgery. FUNDING: EU/European Federation of Pharmaceutical Industries and Associations Innovative Medicines Initiative (2) Joint Undertaking (EHDEN).