The best way to assess oedema using T1, T2 mapping or three-dimensional T2-weighted fast-spin-echo triple inversion recovery sequences via cardiovascular MRI in outpatients with suspected myocarditis.

AIM: To evaluated T1-, T2 mapping, and a three-dimensional (3D) T2-weighted fast-spin-echo triple inversion recovery sequences (3D STIR) for diagnosing myocardial oedema in patients with suspected early myocarditis and at follow-up. MATERIALS AND METHODS: Sixteen patients with suspected myocarditis and 15 controls matched for gender and age were examined prospectively. To evaluate oedema, an electrocardiogram-triggered T1 and T2 mapping with a gradient spin echo technique and 3D STIR sequences were used to cover the entire left ventricle. The signal intensity ratio (heart muscle in relation to skeletal muscle) was calculated (3D STIR ratio). All patients underwent repeat examinations at follow-up. RESULTS: The mean 3D-STIR ratio was 2.14±0.45 at the patients' initial examination as compared to the control patients' 1.54±0.18 in (p=0.0001) and 1.75±0.16 in patients at follow-up (p=0.002 versus first visit). The 3D STIR ratio of the septum, anterior, lateral, and inferior wall also differed significantly between patients and controls. No significant difference was observed in T1 and T2 mapping between patients and controls at baseline and patients at follow-up. CONCLUSIONS: A significantly higher global signal intensity ratio with 3D-STIR was identified in patients with suspected myocarditis compared to controls, and a significant change during follow-up. No significant difference was detected in T1-, T2 mapping between patients and controls, or between the initial examination and follow-up of patients. The global 3D-STIR ratio may therefore be useful for the diagnosis of myocarditis and should be explored further.

Methadone Matters: What the United States Can Learn from the Global Effort to Treat Opioid Addiction.

In the midst of an opioid epidemic, mortality related to opioid overdose continues to rise in the US. Medications to treat opioid use disorder, including methadone and buprenorphine, are highly effective in reducing the morbidity and mortality related to illicit opioid use. Despite the efficacy of these life-saving medications, the majority of people with an opioid use disorder lack access to treatment. This paper briefly reviews the evidence to support the use of medications to treat opioid use disorder with a specific focus on methadone. We discuss the current state of methadone therapy for the treatment of opioid use disorder in the US and present logistical barriers that limit its use. Next, we examine three international pharmacy-based models in which methadone dispensing to treat opioid use disorder occurs outside of an opioid treatment facility. We discuss current challenges and opportunities to incorporate similar methods of methadone dispensing for the treatment of opioid use disorder in the US. Finally, we present our vision to integrate pharmacy-based methadone dispensing into routine opioid use disorder treatment through collaboration between clinicians and pharmacies to improve local access to this life-saving medication.

The origin of ultra diffuse galaxies: stellar feedback and quenching.

We test if the cosmological zoom-in simulations of isolated galaxies from the FIRE project reproduce the properties of ultra diffuse galaxies (UDGs). We show that outflows that dynamically heat galactic stars, together with a passively aging stellar population after imposed quenching, naturally reproduce the observed population of red UDGs, without the need for high spin haloes, or dynamical influence from their host cluster. We reproduce the range of surface brightness, radius, and absolute magnitude of the observed red UDGs by quenching simulated galaxies at a range of different times. They represent a mostly uniform population of dark matter-dominated dwarf galaxies with M * ~ 108 M☉, low metallicity, and a broad range of ages; the more massive the UDGs, the older they are. The most massive red UDG in our sample(M * ~ 3 × 108 M☉) requires quenching at z ~ 3 when its halo reached M h ~ 1011M☉. Our simulated UDGs form with normal stellar-to-halo ratios and match the central enclosed masses and the velocity dispersions of the observed UDGs. Enclosed masses remain largely fixed across a broad range of quenching times because the central regions of their dark matter haloes complete their growth early. If our simulated dwarfs are not quenched, they evolve into bluer low surface brightness galaxies with M/L similar to observed field dwarfs. While our simulation sample covers a limited range of formation histories and halo masses, we predict that UDG is a common, and perhaps even dominant, galaxy type around M * ~ 108 M☉, both in the field and in clusters.

Recovering Quantum Gates from Few Average Gate Fidelities.

Characterizing quantum processes is a key task in the development of quantum technologies, especially at the noisy intermediate scale of today's devices. One method for characterizing processes is randomized benchmarking, which is robust against state preparation and measurement errors and can be used to benchmark Clifford gates. Compressed sensing techniques achieve full tomography of quantum channels essentially at optimal resource efficiency. In this Letter, we show that the favorable features of both approaches can be combined. For characterizing multiqubit unitary gates, we provide a rigorously guaranteed and practical reconstruction method that works with an essentially optimal number of average gate fidelities measured with respect to random Clifford unitaries. Moreover, for general unital quantum channels, we provide an explicit expansion into a unitary 2-design, allowing for a practical and guaranteed reconstruction also in that case. As a side result, we obtain a new statistical interpretation of the unitarity-a figure of merit characterizing the coherence of a process.

Early diastolic septal movement in patients with myocarditis.

AIM: To evaluate early diastolic septal relaxation as a parameter in the diagnostic workup via cardiovascular magnetic resonance imaging (CMRI) in patients with myocarditis. MATERIALS AND METHODS: Early diastolic septal movement was evaluated (EDS) prospectively via frame-by-frame analysis in 255 consecutive patients with presenting signs of myocarditis and in 64 controls matched 4:1 for gender and age. ECG-triggered, T2-weighted, fast spin echo triple inversion recovery sequences and late gadolinium enhancement were obtained, as well as left ventricular (LV) function and dimensions in patients and controls. RESULTS: EDS was detected in 66.7% of the patients and 18.7% of the controls (p<0.001). Sensitivity was 69.4% and specificity 79.7%. Patients with EDS had a significant lower LV ejection fraction (LV-EF) of 61.1±0.6% and significant higher end-diastolic volume (EDV) of 158.5±2.7 ml than in patients without EDS (LV-EF 65.3±0.9%, p=0.0001; EDV 148.4±3.9 ml, p=0.04). A significant negative correlation was observed between LV-EF and EDS in patients, and a lower LV-EF correlated with a more frequent occurrence of EDS (r=-0.24, p=0.0001). Scar tissue was also more frequent in patients than controls (63.1% and 7.8%, p=0.007). CONCLUSIONS: EDS is a parameter obtained non-invasively by CMRI and is present in a high percentage of patients with myocarditis. Cardiac functional parameters are significantly altered in patients with EDS. EDS is a feasible parameter that can play an important role in the diagnosis of myocarditis.

Sustained Posttransplantation Diabetes Is Associated With Long-Term Major Cardiovascular Events Following Liver Transplantation.

Cardiovascular disease is a leading cause of death among liver transplant (LT) recipients. With a rising burden of posttransplantation metabolic disease, increases in cardiovascular-related morbidity and mortality may reduce life expectancy after LT. It is unknown if the risk of long-term major cardiovascular events (MCEs) differs among LT recipients with varying diabetic states. We performed a retrospective cohort study of LT recipients from 2003 through 2013 to compare the incidence of MCEs among patients (1) without diabetes, (2) with pretransplantation diabetes, (3) with de novo transient posttransplantation diabetes, and (4) with de novo sustained posttransplantation diabetes. We analyzed 994 eligible patients (39% without diabetes, 24% with pretransplantation diabetes, 16% with transient posttransplantation diabetes, and 20% with sustained posttransplantation diabetes). Median follow-up was 54.7 months. Overall, 12% of patients experienced a MCE. After adjustment for demographic and clinical variables, sustained posttransplantation diabetes was the only state associated with a significantly increased risk of MCEs (subdistribution hazard ratio 1.95, 95% confidence interval 1.20-3.18). Patients with sustained posttransplantation diabetes mellitus had a 13% and 27% cumulative incidence of MCEs at 5 and 10 years, respectively. While pretransplantation diabetes has traditionally been associated with cardiovascular disease, the long-term risk of MCEs is greatest in LT recipients with sustained posttransplantation diabetes mellitus.

Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for Pharmacogenetics-Guided Warfarin Dosing: 2017 Update.

This document is an update to the 2011 Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for CYP2C9 and VKORC1 genotypes and warfarin dosing. Evidence from the published literature is presented for CYP2C9, VKORC1, CYP4F2, and rs12777823 genotype-guided warfarin dosing to achieve a target international normalized ratio of 2-3 when clinical genotype results are available. In addition, this updated guideline incorporates recommendations for adult and pediatric patients that are specific to continental ancestry.

Warfarin pharmacogenomics: current best evidence.

The utility of using genetic information to guide warfarin dosing has remained unclear based on prior observational studies and small clinical trials. Two larger trials of warfarin and one of the acenocoumarol and phenprocoumon have recently been published. The COAG trial addressed the incremental benefit of adding genetic information to clinical information and demonstrated no benefit from the pharmacogenetic-based dosing strategy on the primary outcome. The EU-PACT UK trial compared an algorithm approach using genetic and clinical information to one that used a relatively fixed starting dose. The pharmacogenetic-based algorithms improved the primary outcome. The study of acenocoumarol and phenprocoumon compared a pharmacogenetic with a clinical algorithm and demonstrated no benefit on the primary outcome. The evidence to date does not support an incremental benefit of adding genetic information to clinical information on anticoagulation control. However, compared with fixed dosing, a pharmacogenetic algorithm can improve anticoagulation control.

Risk of myocardial infarction associated with chronic hepatitis C virus infection: a population-based cohort study.

Hepatitis C virus (HCV) infection is associated with systemic inflammation and metabolic complications that might predispose patients to atherosclerosis. However, it remains unclear if HCV infection increases the risk of acute myocardial infarction (MI). To determine whether HCV infection is an independent risk factor for acute MI among adults followed in general practices in the United Kingdom (UK), a retrospective cohort study was conducted in The Health Improvement Network, from 1996 through 2008. Patients ≥18 years of age with at least 6 months of follow-up and without a prior history of MI were eligible for study inclusion. HCV-infected individuals, identified with previously validated HCV diagnostic codes (n = 4809), were matched on age, sex and practice with up to 15 randomly selected patients without HCV (n = 71 668). Rates of incident MI among patients with and without a diagnosis of HCV infection were calculated. Adjusted hazard ratios were estimated using Cox proportional hazards regression, controlling for established cardiovascular risk factors. During a median follow-up of 3.2 years, there was no difference in the incidence rates of MI between HCV-infected and -uninfected patients (1.02 vs 0.92 events per 1000 person-years; P = 0.7). HCV infection was not associated with an increased risk of incident MI (adjusted HR, 1.10; 95% confidence interval [CI], 0.67-1.83). Sensitivity analyses including the exploration of a composite outcome of acute MI and coronary interventions yielded similar results (adjusted HR, 1.16; 95% CI, 0.77-1.74). In conclusion, HCV infection was not associated with an increased risk of incident MI.

Clinical Pharmacogenetics Implementation Consortium Guidelines for CYP2C9 and VKORC1 genotypes and warfarin dosing.

Warfarin is a widely used anticoagulant with a narrow therapeutic index and large interpatient variability in the dose required to achieve target anticoagulation. Common genetic variants in the cytochrome P450-2C9 (CYP2C9) and vitamin K-epoxide reductase complex (VKORC1) enzymes, in addition to known nongenetic factors, account for ~50% of warfarin dose variability. The purpose of this article is to assist in the interpretation and use of CYP2C9 and VKORC1 genotype data for estimating therapeutic warfarin dose to achieve an INR of 2-3, should genotype results be available to the clinician. The Clinical Pharmacogenetics Implementation Consortium (CPIC) of the National Institutes of Health Pharmacogenomics Research Network develops peer-reviewed gene-drug guidelines that are published and updated periodically on http://www.pharmgkb.org based on new developments in the field.(1).

Validity of The Health Improvement Network (THIN) for the study of psoriasis.

BACKGROUND: Psoriasis is a common disease frequently studied in large databases. To date the validity of psoriasis information has not been established in The Health Improvement Network (THIN). OBJECTIVES: To investigate the validity of THIN for identifying patients with psoriasis and to determine if the database can be used to determine the natural history of the disease. METHODS: First, we conducted a cross-sectional study to determine if psoriasis prevalence in THIN is similar to expected. Second, we created a cohort of 4900 patients, aged 45-64 years, with a psoriasis diagnostic Read Code and surveyed their general practitioners (GPs) to confirm the diagnosis clinically. Third, we created models to determine if psoriasis descriptors (extent, severity, duration and dermatologist confirmation) could be accurately captured from database records. RESULTS: Psoriasis prevalence was 1·9%, and showed the characteristic age distribution expected. GP questionnaires were received for 4634 of 4900 cohort patients (95% response rate), and psoriasis diagnoses were confirmed in 90% of patients. Duration of disease in the database showed substantial agreement with physician query (κ = 0·69). GPs confirmed that the psoriasis diagnosis was corroborated by a dermatologist in 91% of patients whose database records contained a dermatology referral code associated with a psoriasis code. We achieved good discrimination between patients with and without extensive disease based on the number of psoriasis codes received per year (area under curve = 0·8). CONCLUSIONS: THIN is a valid data resource for studying psoriasis and can be used to identify characteristics of the disease such as duration and confirmation by a dermatologist.

Integration of genetic, clinical, and INR data to refine warfarin dosing.

Well-characterized genes that affect warfarin metabolism (cytochrome P450 (CYP) 2C9) and sensitivity (vitamin K epoxide reductase complex 1 (VKORC1)) explain one-third of the variability in therapeutic dose before the international normalized ratio (INR) is measured. To determine genotypic relevance after INR becomes available, we derived clinical and pharmacogenetic refinement algorithms on the basis of INR values (on day 4 or 5 of therapy), clinical factors, and genotype. After adjusting for INR, CYP2C9 and VKORC1 genotypes remained significant predictors (P < 0.001) of warfarin dose. The clinical algorithm had an R(2) of 48% (median absolute error (MAE): 7.0 mg/week) and the pharmacogenetic algorithm had an R(2) of 63% (MAE: 5.5 mg/week) in the derivation set (N = 969). In independent validation sets, the R(2) was 26-43% with the clinical algorithm and 42-58% when genotype was added (P = 0.002). After several days of therapy, a pharmacogenetic algorithm estimates the therapeutic warfarin dose more accurately than one using clinical factors and INR response alone.

Estimation of the warfarin dose with clinical and pharmacogenetic data.

BACKGROUND: Genetic variability among patients plays an important role in determining the dose of warfarin that should be used when oral anticoagulation is initiated, but practical methods of using genetic information have not been evaluated in a diverse and large population. We developed and used an algorithm for estimating the appropriate warfarin dose that is based on both clinical and genetic data from a broad population base. METHODS: Clinical and genetic data from 4043 patients were used to create a dose algorithm that was based on clinical variables only and an algorithm in which genetic information was added to the clinical variables. In a validation cohort of 1009 subjects, we evaluated the potential clinical value of each algorithm by calculating the percentage of patients whose predicted dose of warfarin was within 20% of the actual stable therapeutic dose; we also evaluated other clinically relevant indicators. RESULTS: In the validation cohort, the pharmacogenetic algorithm accurately identified larger proportions of patients who required 21 mg of warfarin or less per week and of those who required 49 mg or more per week to achieve the target international normalized ratio than did the clinical algorithm (49.4% vs. 33.3%, P<0.001, among patients requiring < or = 21 mg per week; and 24.8% vs. 7.2%, P<0.001, among those requiring > or = 49 mg per week). CONCLUSIONS: The use of a pharmacogenetic algorithm for estimating the appropriate initial dose of warfarin produces recommendations that are significantly closer to the required stable therapeutic dose than those derived from a clinical algorithm or a fixed-dose approach. The greatest benefits were observed in the 46.2% of the population that required 21 mg or less of warfarin per week or 49 mg or more per week for therapeutic anticoagulation.

Warfarin with fluoroquinolones, sulfonamides, or azole antifungals: interactions and the risk of hospitalization for gastrointestinal bleeding.

The aim of this study was to determine whether a potential pharmacokinetic interaction between warfarin and orally administered anti-infectives increases the risk of hospitalization for gastrointestinal (GI) bleeding in warfarin users. We conducted a nested case-control and case-crossover study using US Medicaid data. Logistic regression was used to determine the association between GI bleeding and prior use of ciprofloxacin, levofloxacin, gatifloxacin, co-trimoxazole, or fluconazole vs. no exposure and also vs. use of cephalexin, which would not be expected to interact with warfarin. All of the anti-infectives examined were associated with elevated odds ratios (ORs) when compared to no exposure to these drugs. With cephalexin data as the reference, the ORs for co-trimoxazole (OR: 1.68 (95% confidence interval (CI): 1.21-2.33) in the prior 6-10 days) and fluconazole (OR: 2.09 (95% CI: 1.34-3.26) in the prior 11-15 days) were significantly elevated. Warfarin users who had received an anti-infective agent showed a substantially increased risk of GI bleeding. However, a drug-drug interaction with warfarin was evident only for co-trimoxazole and fluconazole.

Dosing algorithms to predict warfarin maintenance dose in Caucasians and African Americans.

The objective of this study was to determine whether warfarin dosing algorithms developed for Caucasians and African Americans on the basis of clinical, environmental, and genetic factors will perform better than an empirical starting dose of 5 mg/day. From April 2002 through December 2005, 259 subjects (Caucasians and African Americans) who started using warfarin were prospectively followed until they reached maintenance dose. The Caucasian algorithm included 11 variables (R(2) = 0.43). This model (which predicted 51% of the doses to within 1 mg of the observed dose) performed better than 5 mg/day (which predicted 29% of the doses to within 5 +/- 1 mg). The African-American algorithm included 10 variables (R(2) = 0.28). This model predicted 37% of the doses to within 1 mg of the observed dose, representing a small improvement compared with 5 mg/day (which predicted 34% of the doses to within 1 mg of 5 mg/day). These results were similar to the results we obtained from testing other published algorithms. The dosing algorithms explained <45% of the observed variability in Caucasians, and the algorithms performed only marginally better for African Americans when compared with giving 5 mg empirically.

[Sporadic lymphangioleiomyomatosis. Clinical and lung functional characteristics of 32 female patients]. / Sporadische Lymphangioleiomyomatose. Klinische und lungenfunktionelle Charakteristika von 32 Patientinnen.

BACKGROUND AND OBJECTIVE: Lymphangioleiomyomatosis (LAM) is a rare and progressive multi-systemic disorder almost exclusively of women. Clinical and lung functional data of a substantial number of German patients have not so far been published. PATIENTS AND METHODS: In 32 women with sporadic LAM we performed the following investigations: medical history, clinical examination, lung function (spirometry, bodyplethysmography, diffusion capacity for carbon monoxide), ECG, echocardiography, and abdominal ultrasound. RESULTS: The mean age at the time of investigation was 48 (25 - 66) years, while the mean age at time of diagnosis had been 45 (21 - 61) years. The median time between onset of first symptoms and diagnosis was 8 years (1 months - 30 years). Most frequently stated first symptom was dyspnea on exertion (12/32 patients) and the most frequently stated first clinical sign was pneumothorax (12/32). Changes of hormonal status (contraception, treatment for fertility, pregnancy) occurred in 31 of the 32 patients before onset of first symptoms or clinical signs. Hormonal (16/32) and antiobstructive therapy (16/32) were the most frequently applied forms of treatment. Airway obstruction (26/32 patients), hyperinflation (20/32) and reduced diffusion capacity for carbon monoxide (24/32) were found on lung function test. Abnormal auscultation (6 patients), ECG signs of chronic cor pulmonale (4/32) and an elevated systolic pulmonary artery pressure (2 patients) were rare findings. Abdominal lesions (angiomyolipoma, 11/32 patients; lymphangioleiomyoma, 4 patients) were common. CONCLUSION: Lymphangioleiomyomatosis should be considered in women with spontaneous pneumothorax, unexplainable dyspnoea or angiomyolipoma.

[Syncope. A diagnostic challenge]. / Synkope. Eine diagnostische Herausforderung.

Approximately 40% of people have experienced a syncopal attack during their lifetime. If the possible causes of syncope are known, the variety of diagnostic procedures can be used efficiently. The European guidelines on the management of syncope recommend a structured diagnostic work-up and distinguish between initial and secondary diagnostic steps. With the basic diagnostic methods, true syncope can be differentiated from other non-syncopal conditions of loss of consciousness. With basic diagnostics it is possible to demonstrate clinical settings, which require emergency treatment, and unnecessary, expensive and time-consuming further diagnostics may be avoided. We provide an algorithm on how to proceed to determine the various reasons for syncope.

Apolipoprotein E genotype and warfarin dosing among Caucasians and African Americans.

Warfarin sodium is a vitamin K antagonist that is plagued by large variability in patient response, including higher dose requirements among African Americans. Polymorphisms in the gene encoding apolipoprotein E (APOE) may partly explain this variability by altering transport of vitamin K to the liver. In a prospective cohort study of 232 individuals (52.2% Caucasian and 47.8% African American) initiating warfarin therapy, the weekly maintenance dose was significantly higher for African Americans than for Caucasians (mean 42.9 versus mean 36.9 mg, P=0.018), and the epsilon4 allele was more common among African Americans (37.8 versus 26.4% for Caucasians). In multivariable analyses, the presence of the epsilon4 allele was associated with a statistically significantly higher warfarin dose among African Americans (median 45.0 mg in epsilon4 carriers versus 35.0 mg in non-epsilon4 carriers, P=0.014) but not Caucasians (38.1 versus 35.0 mg, P=0.60). In addition, warfarin maintenance dose increased among African Americans according to genotype previously associated with differential hepatic chylomicron clearance (epsilon2/epsilon2 or epsilon2/epsilon3: 30.0 mg; epsilon3/epsilon3: 35.0 mg; epsilon3/epsilon4 or epsilon4/epsilon4: 45.0 mg; P=0.012), although the epsilon4/epsilon4 genotype was rare and not clearly associated with higher doses. The association of APOE with warfarin dosing was independent of CYP2C9 and VKORC1 polymorphisms. APOE polymorphisms thus may be important determinants of warfarin maintenance dose and could explain at least some of the observed racial differences in dose requirements.

Warfarin response and vitamin K epoxide reductase complex 1 in African Americans and Caucasians.

The objective of this study was to determine whether two vitamin K epoxide reductase complex 1 (VKORC1) polymorphisms contribute to the variability in warfarin response, particularly in African Americans. The effect of the VKORC1 1173C/T and -1639G/A polymorphisms was examined in a prospective cohort study of 338 warfarin users. Subjects carrying an 1173T allele had a lower warfarin maintenance dose compared with subjects with the CC genotype in African Americans (-12.10 mg/week+/-4.93; P=0.02) and Caucasians (-14.41 mg/week+/-3.28; P<0.001). Before reaching maintenance dose, only Caucasians with the T allele had significantly increased risk of international normalized ratio >3 (odds ratio=3.10; 95% confidence interval: 1.73-5.55) compared with Caucasians with the CC genotype. Polymorphisms in the VKORC1 gene are associated with warfarin maintenance dose requirements among both African Americans and Caucasians. However, these polymorphisms may not be as useful in predicting over-anticoagulation among African Americans.